1H-imidazo[4,5-d]pyridazin-7-one, and corresponding thiones as corticotropin releasing factor (CRF) receptor ligands

ABSTRACT

Corticotropin releasing factor (CRF) antagonists of formula I:                    
     and their use in treating anxiety, depression, and other psychiatric, neurological disorders as well as treatment of immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disturbance and stress.

This application is a division of U.S. Ser. No. 09/473,870, filed Dec.28, 1999, now U.S. Pat. No. 6,271,380 which is a continuation of U.S.Provisional Application Ser. No. 60/114,188, filed Dec. 30, 1998.

FIELD OF THE INVENTION

This invention relates a treatment of psychiatric disorders andneurological diseases including major depression, anxiety-relateddisorders, post-traumatic stress disorder, supranuclear palsy andfeeding disorders as well as treatment of immunological, cardiovascularor heart-related diseases and colonic hypersensitivity associated withpsychopathological disturbance and stress, by administration of certain1H-imidazo[4,5-d]pyridazin-7-ones, 3H-imidazo-[4,5-c]pyridin-4-ones andcorresponding thiones.

BACKGROUND OF THE INVENTION

Corticotropin releasing factor (herein referred to as CRF), a 41 aminoacid peptide, is the primary physiological regulator ofproopiomelanocortin (POMC)-derived peptide secretion from the anteriorpituitary gland [J. Rivier et al., Proc. Nat. Acad. Sci. (USA) 80:4851(1983); W. Vale et al., Science 213:1394 (1981)]. In addition to itsendocrine role at the pituitary gland, immunohistochemical localizationof CRF has demonstrated that the hormone has a broad extrahypothalamicdistribution in the central nervous system and produces a wide spectrumof autonomic, electrophysiological and behavioral effects consistentwith a neurotransmitter or neuromodulator role in brain [W. Vale et al.,Rec. Prog. Horm. Res. 39:245 (1983); G. F. Koob, Persp. Behav. Med. 2:39(1985); E. B. De Souza et al., J. Neurosci. 5:3189 (1985)]. There isalso evidence that CRF plays a significant role in integrating theresponse of the immune system to physiological, psychological, andimmunological stressors [J. E. Blalock, Physiological Reviews 69:1(1989); J. E. Morley, Life Sci. 41:527 (1987)].

Clinical data provide evidence that CRF has a role in psychiatricdisorders and neurological diseases including depression,anxiety-related disorders and feeding disorders. A role for CRF has alsobeen postulated in the etiology and pathophysiology of Alzheimersdisease, Parkinsons disease, Huntingtons disease, progressivesupranuclear palsy and amyotrophic lateral sclerosis as they relate tothe dysfunction of CRF neurons in the central nervous system [for reviewsee E. B. De Souza, Hosp. Practice 23:59 (1988)].

In affective disorder, or major depression, the concentration of CRF issignificantly increased in the cerebral spinal fluid (CSF) of drug-freeindividuals [C. B. Nemeroff et al., Science 226:1342 (1984); C. M. Bankiet al., Am. J. Psychiatry 144:873 (1987); R. D. France et al., Biol.Psychiatry 28:86 (1988); M. Arato et al., Biol Psychiatry 25:355(1989)]. Furthermore, the density of CRF receptors is significantlydecreased in the frontal cortex of suicide victims, consistent with ahypersecretion of CRF [C. B. Nemeroff et al., Arch. Gen. Psychiatry45:577 (1988)]. In addition, there is a blunted adrenocorticotropin(ACTH) response to CRF (i.v. administered) observed in depressedpatients [P. W. Gold et al., Am J. Psychiatry 141:619 (1984); F.Holsboer et al., Psychoneuroendocrinology 9:147 (1984); P. W. Gold etal., New Eng. J. Med. 314:1129 (1986)]. Preclinical studies in rats andnon-human primates provide additional support for the hypothesis thathypersecretion of CRF may be involved in the symptoms seen in humandepression [R. M. Sapolsky, Arch. Gen. Psychiatry 46:1047 (1989)]. Thereis preliminary evidence that tricyclic antidepressants can alter CRFlevels and thus modulate the numbers of CRF receptors in brain[Grigoriadis et al., Neuropsychopharmacology 2:53 (1989)].

There has also been a role postulated for CRF in the etiology ofanxiety-related disorders. CRF produces anxiogenic effects in animalsand interactions between benzodiazepine/non-benzodiazepine anxiolyticsand CRF have been demonstrated in a variety of behavioral anxiety models[D. R. Britton et al., Life Sci. 31:363 (1982); C. W. Berridge and A. J.Dunn Regul. Peptides 16:83 (1986)]. Preliminary studies using theputative CRF-receptor antagonist a-helical ovine CRF (9-41) in a varietyof behavioral paradigms demonstrate that the antagonist producesanxiolytic-likeeffects that are qualitatively similar to thebenzodiazepines [C. W. Berridge and A. J. Dunn Horm. Behav. 21:393(1987), Brain Research Reviews 15:71 (1990)]. Neurochemical, endocrineand receptor binding studies have all demonstrated interactions betweenCRF and benzodiazepine anxiolytics providing further evidence for theinvolvement of CRF in these disorders. Chlordiazepoxide attenuates theanxiogenic effects of CRF in both the conflict test [K. T. Britton etal., Psychopharmacology 86:170 (1985); K. T. Britton et al.,Psychopharmacology 94:306 (1988)] and in the acoustic startle test [N.R. Swerdlow et al., Psychopharmacology 88:147 (1986)] in rats. Thebenzodiazepine receptor antagonist (Ro15-1788), which was withoutbehavioral activity alone in the operant conflict test, reversed theeffects of CRF in a dose-dependent manner while the benzodiazepineinverse agonist (FG7142) enhanced the actions of CRF [K. T. Britton etal., Psychopharmacology 94:306 (1988)].

The mechanisms and sites of action through which the standardanxiolytics and antidepressants produce their therapeutic effects remainto be elucidated. It has been hypothesized however, that they areinvolved in the suppression of the CRF hypersecretion that is observedin these disorders. Of particular interest is that preliminary studiesexamining the effects of a CRF receptor antagonist (α-helical CRF₉₋₄₁)in a variety of behavioral paradigms have demonstrated that the CRFantagonist produces anxiolytic-like effects qualitatively similar to thebenzodiazepines [for review see G. F. Koob and K. T. Britton, In:Corticotropin-Releasing Factor: Basic and Clinical Studies of aNeuropeptide, E. B. De Souza and C. B. Nemeroff eds., CRC Press p221(1990)].

Several publications describe corticotropin releasing factor antagonistcompounds and their use to treat psychiatric disorders and neurologicaldiseases. Examples of such publications include DuPont Merck PCTapplication US94/11050, Pfizer WO 95/33750, Pfizer WO 95/34563, PfizerWO 95/33727 and Pfizer EP 0778 277 A1.

SUMMARY OF THE INVENTION

In accordance with one aspect, the present invention provides novelcompounds, pharmaceutical compositions and methods which may be used inthe treatment of affective disorder, anxiety, depression, irritablebowel syndrome, post-traumatic stress disorder, supranuclear palsy,immune suppression, Alzheimer's disease, gastrointestinal disease,anorexia nervosa or other feeding disorder, drug or alcohol withdrawalsymptoms, drug addiction, inflammatory disorder, fertility problems,disorders, the treatment of which can be effected or facilitated byantagonizing CRF, including but not limited to disorders induced orfacilitated by CRF, or a disorder selected from inflammatory disorderssuch as rheumatoid arthritis and osteoarthritis, pain, asthma, psoriasisand allergies; generalized anxiety disorder; panic, phobias,obsessive-compulsive disorder; post-traumatic stress disorder; sleepdisorders induced by stress; pain perception such as fibromyalgia; mooddisorders such as depression, including major depression, single episodedepression, recurrent depression, child abuse induced depression, andpostpartum depression; dysthemia; bipolar disorders; cyclothymia;fatigue syndrome; stress-induced headache; cancer, humanimmunodeficiency virus (HIV) infections; neurodegenerative diseases suchas Alzheimer's disease, Parkinson's disease and Huntington's disease;gastrointestinal diseases such as ulcers, irritable bowel syndrome,Crohn's disease, spastic colon, diarrhea, and post operative ilius andcolonic hypersensitivity associated by psychopathological disturbancesor stress; eating disorders such as anorexia and bulimia nervosa;hemorrhagic stress; stress-induced psychotic episodes; euthyroid sicksyndrome; syndrome of inappropriate antidiarrhetic hormone (ADH);obesity; infertility; head traumas; spinal cord trauma; ischemicneuronal damage (e.g., cerebral ischemia such as cerebral hippocampalischemia); excitotoxic neuronal damage; epilepsy; cardiovascular andhear related disorders including hypertension, tachycardia andcongestive heart failure; stroke; immune dysfunctions including stressinduced immune dysfunctions (e.g., stress induced fevers, porcine stresssyndrome, bovine shipping fever, equine paroxysmal fibrillation, anddysfunctions induced by confinement in chickens, sheering stress insheep or human-animal interaction related stress in dogs); muscularspasms; urinary incontinence; senile dementia of the Alzheimer's type;multiinfarct dementia; amyotrophic lateral sclerosis; chemicaldependencies and addictions (e.g, dependencies on alcohol, cocaine,heroin, benzodiazepines, or other drugs); drug and alcohol withdrawalsymptoms; osteoporosis; psychosocial dwarfism and hypoglycemia in amammal.

The present invention provides novel compounds which bind tocorticotropin releasing factor receptors, thereby altering theanxiogenic effects of CRF secretion. The compounds of the presentinvention are useful for the treatment of psychiatric disorders andneurological diseases, anxiety-related disorders, post-traumatic stressdisorder, supranuclear palsy and feeding disorders as well as treatmentof immunological, cardiovascular or heart-related diseases and colonichypersensitivity associated with psychopathological disturbance andstress in a mammal.

According to another aspect, the present invention provides novelcompounds of Formula (1) (described below) which are useful asantagonists of the corticotropin releasing factor. The compounds of thepresent invention exhibit activity as corticotropin releasing factorantagonists and appear to suppress CRF hypersecretion. The presentinvention also includes pharmaceutical compositions containing suchcompounds of Formula (1) and methods of using such compounds for thesuppression of CRF hypersecretion, and/or for the treatment ofanxiogenic disorders.

According to yet another aspect of the invention, the compounds providedby this invention (and especially labelled compounds of this invention)are also useful as standards and reagents in determining the ability ofa potential pharmaceutical to bind to the CRF receptor.

DETAILED DESCRIPTION OF INVENTION

[1] The present invention comprises novel compounds of Formula (1)(described below) which are useful as antagonists of the corticotropinreleasing factor. The compounds of the present invention exhibitactivity as corticotropin releasing factor antagonists and appear tosuppress CRF hypersecretion. This invention comprises compounds ofFormula (1):

and isomers thereof, stereoisomeric forms thereof, or mixtures ofstereoisomeric forms thereof, and pharmaceutically acceptable salt orpro-drug forms thereof, wherein:

X is O or S;

A=N or CR⁹;

Ar is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl,furanyl, thienyl, benzothienyl, benzofuranyl, 2,3-dihydrobenzofuranyl,2,3-dihydrobenzothienyl, indanyl, 1,2-benzopyranyl,3,4-dihydro-1,2-benzopyranyl, tetralinyl, each Ar optionally substitutedwith 1 to 5 R⁴ groups and each Ar is attached via an unsaturated carbonatom;

R¹ is independently selected at each occurrence from H, C₁-C₄†alkyl,C₂-C₄†alkenyl, C₂-C₄†alkynyl, halo, CN, C₁-C₄†haloalkyl, C₁-C₁₂hydroxyalkyl, C₂-C₁₂ alkoxyalkyl, C₂-C₁₀ cyanoalkyl, C₃-C₆ cycloalkyl,C₄-C₁₀ cycloalkylalkyl, NR⁹R¹⁰, C₁-C₄ alkyl-NR⁹R¹⁰, NR⁹COR¹⁰, OR¹¹, SHor S(O)_(n)R¹²;

R² is selected from:

—H, aryl, heteroaryl and heterocyclyl, or

—C₁-C₁₀†alkyl, C₂-C₁₀†alkenyl, C₂-C₁₀†alkynyl, C₃-C₈†cycloalkyl, C₅-C₈cycloalkenyl,

C₄-C₁₂†cycloalkylalkyl or C₆-C₁₀ cycloalkenylalkyl, each optionallysubstituted with 1 to 3 substituents independently selected at eachoccurrence from C₁-C₆†alkyl, C₃-C₆†cycloalkyl, C₁₋₆ alkyloxyC₁₋₆ alkyl,C₂₋₆ alkenyl, C₃₋₆ alkynyl, halo, C₁-C₄†haloalkyl, cyano, OR¹⁵, SH,S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵,NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroaryl and heterocyclyl;

R³ is selected from:

—H, aryl, heteroaryl and heterocyclyl, or

C₁-C₄†lkyl, C₃-C₆†alkenyl, C₃-C₆†alkynyl, C₃-C₆†cycloalkyl, C₄-C₁₀cycloalkylalkyl, each optionally substituted with 1 to 3 substituentsindependently selected at each occurrence from C₁-C₆†alkyl,C₃-C₆†cycloalkyl, halo, C₁-C₄†haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹³,COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³,NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroaryl and heterocyclyl;

R⁴ is independently selected at each occurrence from: C₁-C₁₀†alkyl,C₂-C₁₀†alkenyl, C₂-C₁₀†alkynyl, C₃-C₆ cycloalkyl,C₄-C₁₂†cycloalkylalkyl, NO₂, halo, CN, C₁-C₄†haloalkyl, NR⁶R⁷, NR⁶COR⁷,NR⁶CO₂R⁷, COR⁷, OR⁷, CONR⁶R⁷, CO(NOR⁹)R⁷, CO₂R⁷, or S(O)_(n)R⁷, whereeach such C₁-C₁₀†alkyl, C₂-C₁₀†alkenyl, C₂-C₁₀†alkynyl, C₃-C₆ cycloalkyland C₄-C₁₂†cycloalkylalkyl are optionally substituted with 1 to 3substituents independently selected at each occurrence from C₁-C₄ alkyl,NO₂, halo, CN, NR⁶R⁷, NR⁶COR⁷, NR⁶CO₂R⁷, COR⁷ OR⁷, CONR⁶R⁷, CO₂R⁷,CO(NOR⁹)R⁷, or S(O)_(n)R⁷;

R⁶ and R⁷ are independently selected at each occurrence from:

—H,

—C₁-C₁₀ alkyl, C₃-C₁₀ alkenyl, C₃-C₁₀ alkynyl, C₁-C₁₀ haloalkyl with1-10 halogens, C₂-C₈ alkoxyalkyl, C₃-C₆†cycloalkyl,C₄-C₁₂†cycloalkylalkyl, C₅-C₁₀ cycloalkenyl, or C₆-C₁₄cycloalkenylalkyl, each optionally substituted with 1 to 3 substituentsindependently selected at each occurrence from C₁-C₆†alkyl,C₃-C₆†cycloalkyl, halo, C₁-C₄†aloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹³,COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³,NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroaryl or heterocyclyl,

-aryl, aryl(C₁-C₄ alkyl), heteroaryl, heteroaryl(C₁-C₄ alkyl),heterocyclyl or heterocyclyl(C₁-C₄ alkyl);

alternatively, NR⁶R⁷ is piperidine, pyrrolidine, piperazine,N-methylpiperazine, morpholine or thiomorpholine, each optionallysubstituted with 1-3 C₁-C₄ alkyl groups;

R⁸ is independently selected at each occurrence from H or C₁-C₄ alkyloptionally substituted by halogen, C₁-C₄ alkoxy or C₁-C₄ halo-alkoxy (1to 4 halogens);

R⁹ and R¹⁰ are independently selected at each occurrence from H, C₁-C₄alkyl, or C₃-C₆ cycloalkyl;

R¹¹ is selected from H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₃-C₆cycloalkyl;

R¹² is C₁-C₄ alkyl or C₁-C₄ haloalkyl;

R¹³ is selected from C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₂-C₈ alkoxyalkyl,C₃-C₆†cycloalkyl, C₄-C₁₂†cycloalkylalkyl, aryl, aryl(C₁-C₄ alkyl)—,heteroaryl or heteroaryl(C₁-C₄ alkyl)—;

R¹⁵ and R¹⁶ are independently selected at each occurrence from H, C₁-C₆alkyl, C₃-C₁₀ cycloalkyl, C₄-C₁₆ cycloalkylalkyl, except that forS(O)_(n)R¹⁵, R¹⁵ cannot be H;

aryl is phenyl or naphthyl, each optionally substituted with 1 to 5substituents independently selected at each occurrence from C₁-C₆†alkyl,C₃-C₆†cycloalkyl, halo, C₁-C₄†haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹⁵,COR¹⁵, CO₂R¹⁵, OC(O)R¹⁵, NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹⁵,NR¹⁶R¹⁵, and CONR¹⁶R¹⁵;

heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, pyranyl,quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl,pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl,isoxazolyl, pyrazolyl, 2,3-dihydrobenzothienyl or2,3-dihydrobenzofuranyl, each being optionally substituted with 1 to 5substituents independently selected at each occurrence from C₁-C₆†alkyl,C₃-C₆†cycloalkyl, halo, C₁-C₄†haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹⁵,—COR¹⁵, CO₂R¹⁵, OC(O)R¹⁵, NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹⁵,NR¹⁶R¹⁵, and CONR¹⁶R¹⁵;

heterocyclyl is saturated or partially saturated heteroaryl, optionallysubstituted with 1 to 5 substituents independently selected at eachoccurrence from C₁-C₆†alkyl, C₃-C₆†cycloalkyl, halo, C₁-C₄†haloalkyl,cyano, OR¹⁵, SH, S(O)_(n)R¹⁵, COR¹⁵, CO₂R¹⁵, OC(O)R¹⁵, NR⁸COR¹⁵,N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹⁵, NR¹⁵R¹⁶, and CONR¹⁶R¹⁵;

n is independently at each occurrence 0, 1 or 2.

[2] Preferred compounds of the above invention also include compounds ofFormula (1) and isomers thereof, stereoisomeric forms thereof, ormixtures of stereoisomeric forms thereof, and pharmaceuticallyacceptable salt or pro-drug forms thereof wherein Ar is phenyl orpyridyl, each optionally substituted with 1 to 4 R⁴ substituents.

[3] More preferred compounds of the above invention also includecompounds and isomers thereof of formula 1 wherein A is equal tonitrogen (formula 1a), stereoisomeric forms thereof, or mixtures ofstereoisomeric forms thereof, and pharmaceutically acceptable salt orpro-drug forms thereof.

[4] The present invention also relates to compounds, compositions, andstereoisomeric forms, pharmaceutical salts or pro-drugs thereof wherein,in a compound of formula 1, A is equal to CR⁹ (formula 1b):

[5] More preferred compounds of the invention include those compounds offormula 1 wherein X is equal to oxygen.

[6] More preferred compounds of the above invention also includecompounds and isomers thereof, stereoisomeric forms thereof, or mixturesof stereoisomeric forms thereof, and pharmaceutically acceptable salt orpro-drug forms thereof wherein Ar is phenyl or pyridyl and each Ar isoptionally substituted with 1 to 3 R⁴ substituents.

[7] More preferred compounds of the above invention also includecompounds and isomers thereof, stereoisomeric forms thereof, or mixturesof stereoisomeric forms thereof, and pharmaceutically acceptable salt orpro-drug forms thereof wherein R² is:

C₁-C₁₀†alkyl, C₂-C₁₀†alkenyl, C₂-C₁₀†alkynyl, C₃-C₈†cycloalkyl, C₅-C₈cycloalkenyl, C₄-C₁₂†cycloalkylalkyl or C₆-C₁₀ cycloalkenylalkyl, eachoptionally substituted with 1 to 3 substituents independently selectedat each occurrence from C₁-C₆†alkyl, C₃-C₆†cycloalkyl, halo,C₁-C₄†haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³,NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl,heteroaryl and heterocyclyl.

[8] More preferred compounds also include those compounds of formula 1wherein R¹, R² and R³ are independently selected at each position fromzC₁₋₆ alkyl.

[9] The present invention comprises a method of treating affectivedisorder, anxiety, depression, headache, irritable bowel syndrome,post-traumatic stress disorder, supranuclear palsy, immune suppression,Alzheimer's disease, gastrointestinal diseases, anorexia nervosa orother feeding disorder, drug addiction, drug or alcohol withdrawalsymptoms, inflammatory diseases, cardiovascular or heart-relateddiseases, fertility problems, human immunodeficiency virus infections,hemorrhagic stress, obesity, infertility, head and spinal cord traumas,epilepsy, stroke, ulcers, amyotrophic lateral sclerosis, hypoglycemia ora disorder the treatment of which can be effected or facilitated byantagonizing CRF, including but not limited to disorders induced orfacilitated by CRF, in mammals comprising administering to the mammal atherapeutically effective amount of a compound of Formula (1) with thevariables as recited above.

The present invention also provides pharmaceutical compositionscomprising compounds of Formula (1) with the variables as recited aboveand a pharmaceutically acceptable carrier.

Many compounds of this invention have one or more asymmetric centers orplanes. Unless otherwise indicated, all chiral (enantiomeric anddiastereomeric) and racemic forms are included in the present invention.Many geometric isomers of olefins, C═N double bonds, and the like canalso be present in the compounds, and all such stable isomers arecontemplated in the present invention. The compounds may be isolated inoptically active or racemic forms. It is well known in the art how toprepare optically active forms, such as by resolution of racemic formsor by synthesis from optically active starting materials. All chiral,(enantiomeric and diastereomeric) and racemic forms and all geometricisomeric forms of a structure are intended, unless the specificstereochemistry or isomer form is specifically indicated.

The term “alkyl” includes both branched and straight-chain alkyl havingthe specified number of carbon atoms. Commonly used abbreviations havethe following meanings: Me is methyl, Et is ethyl, Pr is propyl, Bu isbutyl. The prefix “n” means a straight chain alkyl. The prefix “c” meansa cycloalkyl. The prefix “(S)” means the S enantiomer and the prefix“(R)” means the R enantiomer. Alkenyl” includes hydrocarbon chains ofeither a straight or branched configuration and one or more unsaturatedcarbon-carbon bonds which may occur in any stable point along the chain,such as ethenyl, propenyl, and the like. “Alkynyl” includes hydrocarbonchains of either a straight or branched configuration and one or moretriple carbon-carbon bonds which may occur in any stable point along thechain, such as ethynyl, propynyl and the like. “Haloalkyl” is intendedto include both branched and straight-chain alkyl having the specifiednumber of carbon atoms, substituted with 1 or more halogen; “alkoxy”represents an alkyl group of indicated number of carbon atoms attachedthrough an oxygen bridge; “cycloalkyl” is intended to include saturatedring groups, including mono-,bi- or poly-cyclic ring systems, such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and so forth. “Halo”or “halogen” includes fluoro, chloro, bromo, and iodo.

The term “substituted”, as used herein, means that one or more hydrogenon the designated atom is replaced with a selection from the indicatedgroup, provided that the designated atom's normal valency is notexceeded, and that the substitution results in a stable compound. When asubstitent is keto (i.e., ═O), then 2 hydrogens on the atom arereplaced.

Combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds. By “stable compound” or“stable structure” is meant a compound that is sufficiently robust tosurvive isolation to a useful degree of purity from a reaction mixture,and formulation into an efficacious therapeutic agent.

The term “appropriate amino acid protecting group” means any group knownin the art of organic synthesis for the protection of amine orcarboxylic acid groups. Such amine protecting groups include thoselisted in Greene and Wuts, “Protective Groups in Organic Synthesis” JohnWiley & Sons, New York (1991) and “The Peptides: Analysis, Synthesis,Biology, Vol. 3, Academic Press, New York (1981), the disclosure ofwhich is hereby incorporated by reference. Any amine protecting groupknown in the art can be used. Examples of amine protecting groupsinclude, but are not limited to, the following: 1) acyl types such asformyl, trifluoroacetyl, phthalyl, and p-toluenesulfonyl; 2) aromaticcarbamate types such as benzyloxycarbonyl (Cbz) and substitutedbenzyloxycarbonyls, 1-(p-biphenyl)-1-methylethoxycarbonyl, and9-fluorenylmethyloxycarbonyl (Fmoc); 3) aliphatic carbamate types suchas tert-butyloxycarbonyl (Boc), ethoxycarbonyl,diisopropylmethoxycarbonyl, and allyloxycarbonyl; 4) cyclic alkylcarbamate types such as cyclopentyloxycarbonyl and adamantyloxycarbonyl;5) alkyl types such as triphenylmethyl and benzyl; 6) trialkylsilanesuch as trimethylsilane; and 7) thiol containing types such asphenylthiocarbonyl and dithiasuccinoyl.

The term “pharmaceutically acceptable salts” includes acid or base saltsof the compounds of Formulae (1) and (2). Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like.

Pharmaceutically acceptable salts of the compounds of the invention canbe prepared by reacting the free acid or base forms of these compoundswith a stoichiometric amount of the appropriate base or acid in water orin an organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985, p. 1418, the disclosure of which is hereby incorporated byreference.

“Prodrugs” are considered to be any covalently bonded carriers whichrelease the active parent drug of formula (I) or (II) in vivo when suchprodrug is administered to a mammalian subject. Prodrugs of thecompounds of formula (I) and (II) are prepared by modifying functionalgroups present in the compounds in such a way that the modifications arecleaved, either in routine manipulation or in vivo, to the parentcompounds. Prodrugs include compounds wherein hydroxy, amine, orsulfhydryl groups are bonded to any group that, when administered to amammalian subject, cleaves to form a free hydroxyl, amino, or sulfhydrylgroup, respectively. Examples of prodrugs include, but are not limitedto, acetate, formate and benzoate derivatives of alcohol and aminefunctional groups in the compounds of formulas (I) and (II); and thelike.

The term “therapeutically effective amount” of a compound of thisinvention means an amount effective to antagonize abnormal level of CRFor treat the symptoms of affective disorder, anxiety or depression in ahost.

Syntheses

Some compounds of Formula (1) where X=O and A=N, may be prepared fromintermediate compounds of Formula (3) using the procedures outlined inScheme 1. Compounds of Formula (3) may be treated with a halogenatingagent in the presence or absence of a base in the presence or absence ofan inert solvent at reaction temperatures ranging from −80° C. to 250°C. to give products of Formula (4) (where X is halogen). Halogenatingagents include, but are not limited to, Br₂, Cl₂, I₂,N-bromosuccinimide, N-iodosuccinimide or N-chlorosuccinimide. Bases mayinclude, but are not limited to, alkali metal carbonates, alkali metalbicarbonates, trialkyl amines (preferably N,N-di-isopropyl-N-ethylamine) or aromatic amines (preferably pyridine). Inert solvents mayinclude, but are not limited to, lower alkanenitriles (1 to 6 carbons,preferably acetonitrile), dialkyl ethers (preferably diethyl ether),cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane),N,N-dialkylformamides (preferably dimethylformamide),N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides(preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferablydimethylsulfoxide), aromatic hydrocarbons (preferably benzene ortoluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens(preferably dichloromethane). Preferred reaction temperatures range from−20° C. to 150° C. The resulting intermediates (4) may then be reactedwith alcohols R²OH, where R² is defined above, in the presence ofphosphines R^(a) ₃P (where R^(a) is lower alkyl, phenyl or substitutedphenyl or furyl) and an azodicarboxylate ester R^(b)O₂CN═NCO₂R^(b)(where R^(b) is lower alkyl)in an inert solvent at temperatures rangingfrom −80° C. to 150° C. Inert solvents may include, but are not limitedto, polyethers (preferably 1,2-dimethoxyethane), dialkyl ethers(preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or1,4-dioxane) or aromatic hydrocarbons (preferably benzene or toluene).The choices of phosphine, solvent or azodicarboxylate ester are known tothose skilled in the art as described by 0. Mitsunobu (Synthesis, 1[1981]). Intermediates (5) are treated with a base or an alkali metal inan inert solvent and then reacted with formylating agents YCHO. Y is ahalogen, alkoxy, dialkylamino, alkylthio, alkanoyloxy, alkanesulfonyloxyor cyano group. Bases may include, but are not limited to, alkyllithiums, alkali metal hydrides (preferably sodium hydride), alkalineearth metal halides (e.g. methylmagnesium bromide), alkaline earth metalhydrides, alkali metal dialkylamides (preferably lithiumdi-isopropylamide) and alkali metal bis(trialkylsilyl)-amides(preferably sodium bis(trimethylsilyl)amide). Inert solvents include,but are not limited to, dialkyl ethers (preferably diethyl ether),cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), or aromatichydrocarbons (preferably benzene or toluene). Preferred reactiontemperatures range from −80° C. to 100° C.

The resulting aldehydes (6) may be converted to acetals (7) by treatmentwith an acetal-forming reagent in the presence or absence of an acid inan inert solvent. The dotted line between the R groups means that theymay or may not be connected. Acetal-forming reagents may be alcoholsROH, where R is lower alkyl, diols HOR—ROH where R—R is lower alkylene,or orthoesters HC(OR)₃ where R is lower alkyl. Inert solvents mayinclude, but are not limited to, water, alkyl alcohols (1 to 8 carbons,preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons,preferably acetonitrile), cyclic ethers (preferably tetrahydrofuran or1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide),N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides(preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferablydimethylsulfoxide) or aromatic hydrocarbons (preferably benzene ortoluene). Acids may include, but are not limited to alkanoic acids of 2to 10 carbons (preferably acetic acid), haloalkanoic acids (2-10carbons, 1-10 halogens, such as trifluoroacetic acid), arylsulfonicacids (preferably p-toluenesulfonic acid or benzenesulfonic acid),alkanesulfonic acids of 1 to 10 carbons (preferably methanesulfonicacid), hydrochloric acid, sulfuric acid or phosphoric acid.Stoichiometric or catalytic amounts of such acids may be used. Preferredtemperatures range from ambient temperature to 150° C.

Acetals (7) may then be reacted with a base in an inert solvent,followed by treatment with a compound ArCOY (where Y is a halogen,alkoxy, dialkylamino, alkylthio, alkanoyloxy, alkanesulfonyloxy or cyanogroup) to afford intermediates (8). Bases may include, but are notlimited to, alkyl lithiums, alkali metal dialkylamides (preferablylithium di-isopropylamide) or alkali metal bis(trialkylsilyl)amides(preferably sodium bis(trimethylsilyl)amide. Inert solvents may include,but are not limited to, dialkyl ethers (preferably diethyl ether),cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane or aromatichydrocarbons (preferably benzene or toluene). Intermediates (8) may thenbe converted to compounds of Formula (9) by treatment with anacetal-cleaving reagent in an inert solvent. Acetal-cleaving reagentsmay include, but are not limited to, hydrochloric acid, sulfuric acid,phosphoric acid, alkanoic acids, alkylsulfonic acids, substitutedphenylsulfonic acids, camphorsulfonic acid or haloalkylsulfonic acids.Inert solvents may include, but are not limited to, water, alkylalcohols (1 to 8 carbons, preferably methanol or ethanol), loweralkanenitriles (1 to 6 carbons, preferably acetonitrile), cyclic ethers(preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides(preferably dimethylformamide), N,N-dialkylacetamides (preferablydimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one),dialkylsulfoxides (preferably dimethylsulfoxide) or aromatichydrocarbons (preferably benzene or toluene).

The keto-aldehydes (9) may be converted to esters (10) by treatment withan oxidizing agent in an inert solvent to give a carboxylic acid,followed by treatment with an ester-forming reagent. Oxidizing agentsinclude transition metal oxides, such as CrO₃ or KMnO₄ (with or withouta buffering agent such as NaH₂PO₄), pyridinium dichromate orpyridine-SO₃ complex. Inert solvents include water, alkanones (e.g.acetone), aqueous solutions of HCl or H₂SO₄, or N,N-dialkylformamides.Ester-forming reagents include but are not limited to alcohols R^(c)OH,where R^(c) is lower alkyl, or orthoesters HC(OR^(c))₃ or combinationsof a halogenating reagent and an alcohol R^(c)OH used sequentially or inthe same reaction. Halogenating agents include, but are not limited to,POCl₃, (COCl)₂, SOCl₂, N-halosuccinimides, PCl₃, PCl₅ or PBr3. Inertsolvents for the halogenation include, but are not limited to, aromatichydrocarbons (preferably benzene or toluene), aromatic amines (e.g.pyridine) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens(preferably dichloromethane). Preferred reaction temperatures range from0° C. to 150° C.

Alternatively, aldehydes (9) may be reacted with a compound MCN, where Mis H, alkali metal or tetraalkylammonium moiety, in an inert solvent,treated with an oxidizing agent and reacted with alcohols R^(c)OH whereR^(c) is lower alkyl. Oxidizing include, but are not limited to,transition metal oxides, such as CrO₃ or MnO₂, pyridine-chromiumcomplexes, such as CrO₃.C₅H₅N, pyridinium dichromate or pyridiniumchlorochromate or an oxalylchloride-dimethylsulfoxide-triethylaminereagent system, commonly called the Swern oxidation system (D. Swern etal., J. Organic. Chem., 43, 2480-2482 (1978)). Inert solvents of theoxidation include, but are not limited to, halocarbons of 1 to 6carbons, preferably dichloromethane or 1,2-dichloroethane, lower alkylalcohols, preferably ethanol or methanol, or lower alkanoic acids,dialkyl ethers (preferably diethyl ether), cyclic ethers (preferablytetrahydrofuran or 1,4-dioxane), or combinations thereof.

Esters (10) may then be converted to compounds of Formula (1) where X=Oand A=N by one of two methods. Esters (10) may be reacted with hydrazineor its hydrate in an inert solvent, then treated with an alkylatingagent in the presence or absence of a base in an inert solvent toprovide compounds of Formula (1) where X is O and A=N. Phase transfercatalysts (e.g. tetra-alkylammonium halides or hydroxides) may beoptionally employed for the alkylations. Alternatively, esters (10) maybe reacted with compounds of Formula R³NHNH₂ (where R³ is defined above)in the presence or absence of a base in an inert solvent. Alkylatingagents are compounds of the formula R³Z, where Z is halogen,alkanesulfonyloxy (e.g. mesylate), substituted phenylsulfonyloxy (e.g.tosylate) or haloalkanesulfonyloxy (e.g. triflate) groups. Bases mayinclude, but are not limited to, alkali metal carbonates, alkali metalbicarbonates, alkyl lithiums, alkali metal hydrides (preferably sodiumhydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodiummethoxide or sodium ethoxide), alkaline earth metal hydrides, alkalimetal dialkylamides (preferably lithium di-isopropylamide), alkali metalhydroxides, alkali metal bis(trialkylsilyl)amides (preferably sodiumbis(trimethylsilyl)amide), trialkyl amines (preferablyN,N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines(preferably pyridine). Inert solvents may include, but are not limitedto, water, lower alkanenitriles (1 to 6 carbons, preferablyacetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers(preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides(preferably dimethylformamide), N,N-dialkylacetamides (preferablydimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one),dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons(preferably benzene or toluene), haloalkanes of 1 to 10 carbons and 1 to10 halogens (preferably dichloromethane) or combinations thereof.Preferred reaction temperatures range from −80° C. to 100° C.

Compounds of Formula (1) where A=N and X=O may be converted to compoundsof Formula (1) where A=N and X=S according to the procedures outlined inScheme 2. Compounds of Formula (1) where A=N, X=O and R³=H may beconverted to compounds of Formula (1) where A=N, X=S and R³=H bytreatment with a thiocarbonyl-forming reagent in an inert solvent.Thiocarbonyl-forming reagents include but are not limited to, P₂S₅ orLawessons reagent. Inert solvents may include, but are not limited to,lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkylethers (preferably diethyl ether), cyclic ethers (preferablytetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferablydimethylformamide), N,N-dialkylacetamides (preferablydimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one),dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons(preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1to 10 halogens (preferably dichloromethane). Preferred reactiontemperatures range from 0° C. to 160° C. These intermediates may then beconverted to compounds of Formula (1) where A=N, X=S and R³ is not equalto H by treatment with an alkylating agent in the presence or absence ofa base in an inert solvent. Alkylating agents are compounds of theformula R³Z, where Z is halogen, alkanesulfonyloxy (e.g. mesylate),substituted phenylsulfonyloxy (e.g. tosylate) or haloalkanesulfonyloxy(e.g. triflate) groups. Bases may include, but are not limited to,alkali metal carbonates, alkali metal bicarbonates, alkyl lithiums,alkali metal hydrides (preferably sodium hydride), alkali metalalkoxides (1 to 6 carbons) (preferably sodium methoxide or sodiumethoxide), alkaline earth metal hydrides, alkali metal dialkylamides(preferably lithium di-isopropylamide), alkali metalbis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide),trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine ortriethylamine) or aromatic amines (preferably pyridine). Inert solventsmay include, but are not limited to, lower alkanenitriles (1 to 6carbons, preferably acetonitrile), dialkyl ethers (preferably diethylether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane),N,N-dialkylformamides (preferably dimethylformamide),N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides(preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferablydimethylsulfoxide), aromatic hydrocarbons (preferably benzene ortoluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens(preferably dichloromethane). Preferred reaction temperatures range from−80° C. to 150° C. Alternatively, Compounds of Formula (1) where A=N,X=O and R³ is not equal to H may be converted to compounds of Formula(1) where A=N, X=S and R³ is not equal to H by treatment with athiocarbonyl-forming reagent in an inert solvent. The reagent and inertsolvent are defined above.

Compounds of Formula (1) where A=CR⁹ may be prepared from esters (10) bythe methods outlined in Scheme 3. Esters (10) may be treated withphosphonium salts of the formula R^(d) ₃PCH R⁹OR^(f+)X⁻ where R^(d) isphenyl or substituted phenyl or phosphonates (R^(e)O)₂P(O)CHR⁹OR^(f) inthe presence of a base in an inert solvent to give enol ethers (12).Bases may include, but are not limited to, alkali metal carbonates,alkali metal bicarbonates, alkyl lithiums, alkali metal hydrides(preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons)(preferably sodium methoxide or sodium ethoxide), alkaline earth metalhydrides, alkali metal dialkylamides (preferably lithiumdi-isopropylamide), alkali metal bis(trialkylsilyl)amides (preferablysodium bis(trimethylsilyl)amide). Inert solvents include, but are notlimited to, dialkyl ethers (preferably diethyl ether) or cyclic ethers(preferably tetrahydrofuran or 1,4-dioxane). Intermediates (12) may behydrolyzed to give intermediates (13) in the presence of an acid in aninert solvent. Acids may include, but are not limited to alkanoic acidsof 2 to 10 carbons (preferably acetic acid), haloalkanoic acids (2-10carbons, 1-10 halogens, such as trifluoroacetic acid), arylsulfonicacids (preferably p-toluenesulfonic acid or benzenesulfonic acid),alkanesulfonic acids of 1 to 10 carbons (preferably methanesulfonicacid), hydrochloric acid, sulfuric acid or phosphoric acid.Stoichiometric or catalytic amounts of such acids may be used. Preferredtemperatures range from ambient temperature to 150° C. Aldehydes (13)may be treated with amines R³NH₂ to generate compounds of Formula (1)where A=CR⁸ in the presence or absence of an acid or base in an inertsolvent. Acids may include, but are not limited to alkanoic acids of 2to 10 carbons (preferably acetic acid), haloalkanoic acids (2-10carbons, 1-10 halogens, such as trifluoroacetic acid), arylsulfonicacids (preferably p-toluenesulfonic acid or benzenesulfonic acid),alkanesulfonic acids of 1 to 10 carbons (preferably methanesulfonicacid), hydrochloric acid, sulfuric acid or phosphoric acid.Stoichiometric or catalytic amounts of such acids may be used. Bases mayinclude, but are not limited to, alkali metal carbonates, alkali metalbicarbonates, alkyl lithiums, alkali metal hydrides (preferably sodiumhydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodiummethoxide or sodium ethoxide), alkaline earth metal hydrides, alkalimetal dialkylamides (preferably lithium di-isopropylamide), alkali metalbis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide).Inert solvents may include, but are not limited to, water, alkylalcohols (1 to 8 carbons, preferably methanol or ethanol), loweralkanenitriles (1 to 6 carbons, preferably acetonitrile), cyclic ethers(preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides(preferably dimethylformamide), N,N-dialkylacetamides (preferablydimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one),dialkylsulfoxides (preferably dimethylsulfoxide) or aromatichydrocarbons (preferably benzene or toluene). Preferred temperaturesrange from ambient temperature to 150° C.

Alternatively, imidazo[4,5-d]pyridazin-7-ones may be obtained fromintermediate (4) as shown in Scheme 4. The intermediate (4) mayconverted to compound of formula (14) using protecting groups but notlimited to benzyl, p-MeO-benzyl or benzyloxymethyl groups. Compound 14may be converted to compound 20 using the conditions previouslydescribed for Scheme 1. Compound 10 may then be deprotected to its NHderivative (21) by standard conditions known in literature. Compound 21may alkylated under mitsunobu conditions described in Scheme 1 or byalkylation using a base and alkyl halides in the presence of a solvent.

EXAMPLES

Analytical data were recorded for the compounds described below usingthe following general procedures. Proton NMR spectra were recorded on anVarian FT-NMR (300 MHz); chemical shifts were recorded in ppm (δ) froman internal tetramethysilane standard in deuterochloroform ordeuterodimethylsulfoxide as specified below. Mass spectra (MS) or highresolution mass spectra (HRMS) were recorded on a Finnegan MAT 8230spectrometer (using chemi-ionization (CI) with NH₃ as the carrier gas orgas chromatography (GC) as specified below) or a Hewlett Packard 5988Amodel spectrometer. Melting points were recorded on a Buchi Model 510melting point apparatus and are uncorrected. Boiling points areuncorrected. All pH determinations during workup were made withindicator paper.

Reagents were purchased from commercial sources and, where necessary,purified prior to use according to the general procedures outlined by D.Perrin and W. L. F. Armarego, Purification of Laboratory Chemicals, 3rded., (New York: Pergamon Press, 1988). Chromatography (thin layer (TLC)or preparative) was performed on silica gel using the solvent systemsindicated below. For mixed solvent systems, the volume ratios are given.Otherwise, parts and percentages are by weight.

The following examples are provided to describe the invention in furtherdetail. These examples, which set forth the best mode presentlycontemplated for carrying out the invention, are intended to illustrateand not to limit the invention.

Example 14-(2,4-dichlorophenyl)-2-ethyl-1-(1-ethyl)propyl-imidazo[4,5-d]pyridazin-7-one

Part A: 4,5-dibromo-2-ethyl-1H-imidazole

Method A

A solution of 2-ethylimidazole (57.6 g, 0.6 moles) in CHCl₃ (700 mL) wascooled to 0-5° C. and then bromine was added (76.8 mL, 1.5 moles)dropwise over 60 min under nitrogen atmosphere. The mixture was stirredat 5° C. for 60 mins and then at room temperature for 2 days. TLC (1:10MeOH/CH₂Cl₂) revealed disappearance of starting material (Rf=0.25) andshowed a new spot (Rf=0.45). The mixture was cooled back to 0° C. and a2N aq. NaOH solution (750 mL) added dropwise to dissolve the yellowsolid separated from the mixture. The aqueous layer was separated andextracted the organic layer with 250 mL of 2N NaOH. The combined aqueousextracts was acidified to pH 8.0 using a concentrated HCl solution. Thecream-colored solid separated and it was filtered, washed with water anddried in vacuo at 50° C. to afford 55.0 g of desired product (mp149-150° C., 36% yield): ¹H NMR (CDCl₃): δ1.27-1.3 (t, 3H, CH₃), 2.7-2.8(q, 2H, CH₂). Mass spectrum (CI-NH₃) m/z: 255.0 (M+H).

Method B

To a solution of imidazole (2.32 g, 0.0242 moles) in DMF (30.0 mL) wasadded KHCO₃ (6.1 g, 0.061 moles) and then added bromine (3.12 mL, 0.061moles) dropwise over 30 mins. at room temp. The mixture was then stirredat 70° C. for 4 hours and then cooled to room temp. TLC (1:10MeOH/CH₂Cl₂) revealed a new spot (Rf=0.45) along with disappearance ofstarting material (Rf=0.25). The inorganic materials were filtered,washed the inorganic solids with ethyl acetate and concentrated thefiltrate in vacuo to an oil. The oil was treated with water (50.0 mL)and the resulting solid was filtered and dried to afford 4.59 g of asolid ((mp, 149-150° C., 75% yield).

Part B: 4,5-dibromo-2-ethyl-1-(1-ethyl)propyl-1H-imidazole

A mixture of part A material (8.3 g, 0.033 moles), triphenylphosphine(9.4 g, 0.036 moles) and molecular sieves (10 g) in THF (100 mL) wascooled to 0 to −5° C. and then 3-pentanol (3.4 g, 0.039 moles) was addedunder nitrogen atmosphere. The mixture was stirred at 0° C. for 30 minsand then diisopropylazodicarboxylate (7.2 g, 0.033 moles) was addeddropwise over 20 min. The mixture was stirred at 0 ° C. for 2 hoursfollowed by room temperature for 2 days and TLC (1:50 MeOH/CH₂Cl₂)revealed a new spot at Rf=0.5. The reaction mixture was filtered, thecollected solid was washed with dichloromethane and the solvent wasremoved in vacuo to afford yellow liquid. The crude was purified byflash column chromatography using chloroform as eluent to afford 4.9 g(46.5%) of colorless oil. ¹H NMR (CDCl₃): δ0.79-0.84 (t, 6H, 2*CH₃),1.3-1.35 (t, 3H, CH₃), 1.82-2.18 (m, 4H, 2*CH₂), 2.65-2.72 (q, 2H, CH₂),3.95 (m, 1H, CH). Mass spectrum (CINH₃): m/z 325.0 (M+H).

Part C: 4-bromo-2-ethyl-1-(1-ethyl)propyl-1H-imidazole-5-carboxaldehyde

A solution of Part B material (3.7 g, 0.0114 moles) in THF (40.0 mL) wascooled to −78° C. under nitrogen atmosphere and then a 1.6 M n-BuLisolution in hexane (7.4 mL, 0.0119 moles) added dropwise over 30 mins.The mixture was stirred at −78° C. for 1 h and then DMF (2.7 mL, 0.0342moles) was added dropwise over 15 min. The mixture was stirred at −78°C. for 60 min and quenched with saturated NH₄Cl (10 mL) at −78° C. TLC(1:50 MeOH/CH₂Cl₂) revealed a new spot at Rf=0.55 along withdisappearance of starting material spot at Rf=0.5. The reaction mixturewas extracted with diethyl ether (3*25 mL), washed with brine and dried(MgSO₄). The solvent was removed in vacuo to afford a yellow oil whichwas purified by flash column chromatography on silica gel usingchloroform as eluent to afford 1.97 g (64% yield) of colorless oil. ¹HNMR (CDCl₃): δ0.73-0.83 (t, 6H, 2*CH₃), 1.35-1.40 (t, 3H, CH₃),1.59-2.17 (m, 4H, 2*CH₂), 2.72-2.80 (q, 2H, CH₂), 3.95 (m, 1H, CH), 9.67(s, 1H, CHO). Mass spectrum (CI-NH₃): m/z 275.1 (M+2H).

Part D: 4-bromo-2-ethyl-1-(1-ethyl)propyl-1H-imidazole-5-carboxaldehydeethylene glycol acetal

A mixture of part C material (1.75 g, 0.0064 moles) in benzene (150 mL)was treated with ethylene glycol (1.2 mL, 0.025 moles), pyridine (0.0035moles) and p-toluenesulfonic acid mono hydrate (0.0035 moles). Thereaction mixture was heated at reflux in a 20 mL capacity Dean-Starktrap equipped apparatus for 24 hours and TLC (1:50 MeOH/CH₂Cl₂) revealeda new spot at Rf=0.35 (visible under iodine). The reaction mixture wascooled to room temperature, diluted with EtOAc (50 mL), washed with 10%sodium bicarbonate, brine and dried (MgSO₄). The solvent was evaporatedunder reduced pressure to furnish yellow oil. The crude was purified byflash column chromatography on silica gel using 25% ethylacetate/chloroform mixture to afford 1.96 g (97%) white solid (mp 70-71°C.). ¹H NMR (CDCl₃): δ0.78-0.89 (t, 6H, 2*CH₃), 1.29-1.36 (t, 3H, CH₃),1.77-1.90 (m, 4H, 2*CH₂), 2.70-2.73 (q, 2H, CH₂), 3.98-4.3 (m, 5H, CHand 2*CH₂), 5.86 (s, 1H, CH). Mass spectrum (CI-NH₃): 317.1 (M⁺). Anal.calcd. for C₁₃H₂₂Br₁N₂O₂: C, 49.22; H, 6.67; N, 8.83. Found: C, 49.43;H, 6.61; N, 8.78.

Part E:4-(2,4-dichlorobenzoyl)-2-ethyl-1-(1-ethyl)propyl-1H-imidazole-5-carboxaldehyde

A solution of part D material (1.08 g, 0.0034 moles) in THF (20.0 mL)was cooled to −78° C. and then a 1.6 M n-BuLi in hexane (2.4 mL, 0.004moles) was added dropwise over 15 min under nitrogen atmosphere. Themixture was stirred at −78° C. for 2.5 h and then a solution of2,4-dichlorobenzoyl chloride (0.84 g, 0.004 moles) in THF (5.0 mL) wasadded over 15 mins. The mixture was stirred at −78° C. for 6 h followedby room temperature overnight and TLC (30:70 EtOAc/hexane) showed a newspot at Rf=0.43. The mixture was quenched with saturated NH₄Cl (10.0ml), extracted with ethyl acetate (3*30 mL), washed with brine and dried(MgSO₄). The solvent was stripped off in vacuo to afford crude productwhich was purified by flash column chromatography on a silica gel using15% EtOAC/hexane to afford 0.61 g (44% yield) of desired product asyellow oil. Mass spectrum (CI-NH₃): 411.2 (M⁺). The acetal was dissolvedin acetone (15.0 mL) and treated with a 3.0 M aqueous HCl solution (30.0mL) at room temperature. The reaction mixture was stirred for 24 h atthis temperature and TLC (30:70 EtOAc/hexane) showed a new spot atRf=0.55. It was then quenched with saturated NaCl (50.0 ml), extractedwith ethyl acetate (3*50 mL), washed with brine and dried (MgSO₄). Thesolvent was removed in vacuum to afford yellow liquid and purified thecrude by flash column chromatography on a silica gel using 15%EtOAC/hexane to afford 0.28 g (51% yield) of desired product as yellowsolid (mp 85-86° C.). ¹H NMR (CDCl₃): δ0.785 (m, 6H, 2*CH₃), 1.28-1.33(t, 3H, CH₃), 1.90-2.23 (m, 4H, 2*CH₂), 2.74-2.82 (q, 2H, CH₂),3.98-4.05 (m, 1H, CH), 7.34-7.37 (d, 1H, aromatic), 7.45-7.46 (d, 1H,aromatic), 7.55-7.58 (d, 1H, aromatic). Mass spectrum (CI-NH₃): 367(M⁺). Anal. calcd. for C₁₈H₂₀Cl₂N₂O₂: C, 58.87; H, 5.50; N, 7.64. Found:C, 58.91; H, 5.60; N, 7.44.

Part F: Methyl4-(2,4-dichlorobenzoyl)-2-ethyl-1-(1-ethyl)propyl-imidazo-5-carboxylate

A mixture of Part E material (0.367 g, 0.001 moles) in methanol (60 mL)was reacted with NaCN (Aldrich, 0.245 g, 0.005 moles, 5 equiv.), AcOH(Baker, 96 mg; 0.0016 moles, 1.6 equiv.) and MnO₂, activated (Aldrich,1.24 g, 0.021 moles, 21 equiv.). The resulting mixture was stirred atroom temp under nitrogen for 18 h. TLC (1:50 MeOH/CH₂Cl₂) revealedabsence of starting material spot at Rf=0.8 and showed a new spot atRf=0.44. The reaction mixture was filtered through celite, washed withmethanol, concentrated in vacuo and the crude was purified by flashcolumn chromatography on a silica gel using 1:100 MeOH/CH₂Cl₂ as eluentto afford 320 mg (mp 73-74° C., 81%) of white solid aftercrystallization from hexane. Anal. calcd. for C₁₉H₂₂Cl₂N₂O₃: C,57.44;H,5.58; N, 7.05. Found: C,57.31; H,5.45; N,6.85.

Part G: Title Compound

A mixture of Part F material (0.100 g, 0.00025 moles) in ethanol (10 mL)was treated with anhydrous hydrazine (0.105 g, 0.0033 moles) andrefluxed under nitrogen for 48 h. TLC (30:70 EtOAc/hexane) showed a newspot at Rf=0.35. The solvent was removed under vacuum and purified thecrude by flash column chromatography on a silica gel using 15:85EtOAc/hexane initially and then methanol to afford 70 mg (74% yield) ofthe product as white solid after tituration of the oil with diethylether (mp 246-247° C.). HRMS calcd. for C₁₈H₂₁Cl₂N₄O₁: 379.1092. Found:379.1070 (M+H).

Example 24-(2,4-dichlorophenyl)-2-ethyl-1-(1-ethyl)propyl-6-(N-methyl)imidazo[4,5-d]pyridazin-7-one

A mixture of Part F material of example 1 (0.100 g, 0.00025 moles) inethanol (10 mL) was treated with anhydrous methylhydrazine (0.150 g,0.0033 moles) and refluxed under nitrogen for 8 days. TLC (1:50MeOH/CH₂Cl₂) showed a new spot at Rf=0.55. The solvent was removed undervacuum and purified the crude by flash column chromatography on a silicagel 1:50 MeOH/CH₂Cl₂ to afford 30 mg (31% yield) of the product as whitesolid (mp 94-95° C.). HRMS calcd. for C₁₉H₂₃Cl₂N₄O₁: 393.1249. Found:393.1250 (M+H).

Example 34-(2,4-dichlorophnyl)-2-ethyl-6-(N-ethyl)-1-(1-ethyl)propyl-imidazo[4,5-d]pyridazin-7-one

To a solution of Part G of example 1 (0.1 g, 0.264 mmoles) in benzene(5.0 mL) was added n-tetrabutylammonium bromide (8.5 mg, 0.0264 mmoles),powdered KOH (15.0 mg, 0.264 mmoles) and iodoethane (0.124 g, 0.79mmoles). The resultant mixture was stirred at room temperature undernitrogen for 20 h. TLC (1:50 MeOH/CH₂Cl₂) showed a new spot at Rf=0.73along with disappearance of starting material (Rf=0.33). The reactionmixture was diluted with EtOAc (10 mL), washed with brine (10 mL), driedwith MgSO₄ and concentrated to a residue. The crude was purified byflash column chromatography on a silica gel using dichloromethane aseluent to afford 58 mg (54% yield) of the product as colorless oil. HRMScalcd. for C₂₀H₂₅N₄Cl₂O₁: 407.1405. Found: 407.1404 (M+H).

Example 44-(2,4-dichlorophenyl)-2-ethyl-1-(1-ethyl)propyl-6-(N-propyl)-imidazo[4,5-d]pyridazin-7-one

The title compound was prepared using Part G of example 1 material and1-iodopropane and following the conditions outlined in example 3 toafford desired product as colorless oil (56 mg, 51% yield). Anal. calcd.for C₂₁H₂₆N₄Cl₂O₁: C, 59.86; H, 6.23; N, 13.30. Found: C,59.86; H,6.12;N, 13.13.

Example 56-(N-cyclopropylmethyl)-4-(2,4-dichlorophenyl)-2-ethyl-1-(1-ethyl)propyl-imidazo[4,5-d]pyridazin-7-one

The title compound was prepared using Part G of example 1 material andbromomethylcyclopropane and following the conditions outlined in example3 to afford desired product as colorless oil (68 mg, 59% yield). HRMScalcd. for C₂₂H₂₇N₄Cl₂O₁:433.1562. Found: 433.1563 (M+H).

Example 64-Bis(2,4-trifluoromethylphenyl)-2-ethyl-1-(1-ethyl)propyl-6-(N-methyl)-imidazo[4,5-d]pyridazin-7-one

Part A: A solution of part D material of example

1 in THF (30.0 mL) was cooled to −78° C. and then added dropwise 1.6 Mn-BuLi in hexane over 15 mins. The mixture was stirred at −78° C. for 2½h and then added a solution of 2,4-(CF₃)₂—Ph—COCl in 5.0 mL of THF over15 mins. The mixture was stirred at −78° C. for 6 h and then warm toroom temp and stirred overnight. The reaction mixture was quenched witha saturated NH₄Cl solution (50.0 ml), extracted with ethyl acetate (3*30mL), the combined organic extracts were washed with brine and thesolvent was removed under vacuum to afford an orange yellow liquid (4.3g). TLC (30:70 EtOAc/hexane) of the crude showed absence of startingmaterial spot (Rf=0.4) along with a new spot at Rf=0.47. The crude waspurified by flash column chromatography on a silica gel using 30%EtOAC/hexane to afford 1.53 g (mp 105-106° C., 64% yield) of desiredbenzoyl derivative as white solid. Mass spec. (CI-NH₃): 479.2 (M+H).Anal. calcd. for C₂₂H₂₄N₂O₃F₆: C, 55.23; H, 5.07; N, 5.87. Found; C,54.96; H, 5.09; N, 5.72.

Part B: A solution of part A material of example 6 (1.43 g, 2.9 mmoles)in acetone (30.0 mL) was cooled to 15° C. and then added 3M aq. HCl(60.0 mL) over 15 mins. The mixture was stirred below 30° C. for 24 h.TLC (30:70 EtOAc/hexane) showed a new spot at Rf=0.63 along withdisappearance of starting material (Rf=0.43). The solvent was removedunder vacuum, extracted with ethyl acetate (3*50 mL), washed with brineand stripped off the solvent in vacuum to afford yellow liquid. Thecrude was purified by flash column chromatography on a silica gel usingdichloromethane as eluent to afford 1.03 g (82% yield) of desiredaldehyde as yellow liquid. Mass spec. (NH₃-CI): 435 (M+H). Anal. calcd.for C₂₀H₂₀N₂O₂F₆: C, 55.30; H, 4.64; N,6.46. Found; C,55.03; H,4.45;N,6.27.

Part C: A mixture of part B material of example 6 (0.434 g, 1.0 mmole)in methanol (30 mL) was treated with NaCN (Aldrich, 0.245 g, 5.0 mmoles,5 equiv.), AcOH (Baker, 96 mg; 1.6 mmoles, 1.6 equiv.) and MnO₂,activated (Aldrich, 1.24 g, 21.0 mmoles, 21 equiv.). The resultingmixture was stirred at room temp under nitrogen for 24 h. TLC (30:70EtOAc/hexane) revealed absence of starting material at Rf=0.63 andshowed a new spot at Rf=0.55. The reaction mixture was filtered throughcelite, washed with methanol, concentrated in vacuo. The residue wasdiluted with water, extracted with ethyl acetate, washed with brine,dried and concentrated in vacuo to afford yellow oil. The crude waspurified by flash column chromatography on a silica gel using 30:70EtOAc/hexane as eluent to afford 350 mg (mp 57-58° C., 75%) of paleyellow solid. Mass spec. (NH₃-CI) 465.3 (M+H). Anal. calcd. forC₂₁H₂₂N₂O₃F₆: C, 54.31; H, 4.79; N, 6.03. Found: C,53.92; H,4.68; N,5.80.

Part D: Title Compound: A mixture of Part C material of example 6 (0.116g, 0.250 mmoles) in ethylene glycol (3.0 mL) was treated with anhydrousmethylhydrazine (0.15 g, Aldrich, 3.3 mmoles, 13 equiv.) and refluxedunder nitrogen for 20 h. TLC (30:70 EtOAc/hexane) revealed both startingmaterial and product had identical Rf values (0.55). The reactionmixture was cooled to room temperature and poured over 25 mL of water,extracted with EtOAc (3*15 mL), washed with brine and dried. The solventwas removed under vacuo and purified the crude by flash columnchromatography on a silica gel using 30% EtOAc/hexane to afford an oilwhich was crystallized from hexane to afford 16 mg (14% yield; mp139-140° C.) of white solid as desired product. HRMS calcd. forC₂₁H₂₃N₄O₁F₆: 461.1776. Found: 461.1763 (M+H).

Example 7(±)-4-(2,4-dichlorophenyl)-2-ethyl-6-(N-methyl)-1-(1-methyl)butyl-imidazo[4,5-d]pyridazin-7-one

Part A: To a solution of 4,5-dibromo-2-ethyl-1-(2-pentyl)-1H-imidazole(37.5 g, 0.116 moles, prepared according to the method described in PartB of example 1) in THF (250 mL) was cooled to −78° C. and then a 1.6 Mn-BuLi in hexane added dropwise (76.0 mL, 0.122 moles) over 45 mins. Themixture was stirred at −78° C. for 1 h (brown solution) and then addedDMF (27.0 g, 0.348 moles) dropwise over 30 mins. The mixture was stirredat −78° C. for 60 mins. The reaction mixture was quenched with saturatedammonium chloride (100 mL) at −78° C. and brought to room temperature.The reaction mixture was extracted with ethyl ether (3*100 mL), washedwith brine and dried with anhydrous MgSO₄. The solvent was evaporatedunder reduced pressure to afford 31.6 g of crude yellow oil. The crudewas purified by flash column chromatography on a silica gel usingchloroform as eluent to afford 18.5 g (59% yield) of desired aldehyde ascolorless oil. Anal. calcd. for C₁₁H₁₇N₂OBr; C, 48.36; H, 6.27; N,10.25. Found: C,48.64; H,6.01; N,10.00.

Part B: A mixture of part A material of example 7 (18.5 g, 0.068 moles)in benzene (250 mL) was treated with ethylene glycol (16.4 g, 0.264moles), pyridine (2.7 g, 0.034 moles) and p-toluenesulfonic acidmonohydrate (6.5 g, 0.034 moles). The reaction mixture was heated atreflux in a 20 mL capacity Dean-Stark trap equipped apparatus for 36 h.TLC (30:70 EtOAc/hexane) revealed a new spot at Rf=0.42 (visible underiodine) along with disappearance of starting material (Rf=0.54). Thereaction mixture was cooled to room temperature, diluted with EtOAc (250mL), washed with 10% sodium bicarbonate (2*250 mL), brine and dried(MgSO₄). The solvent was evaporated under reduced pressure to furnishacetal as white solid (20.7 g, mp 69-70° C., 96%). Mass spectrum(CI-NH₃): 317.1 (M⁺). Anal. calcd. for C₁₃H₂₂N₂O₂Br₁; C,49.22; H, 6.67,N, 8.83. Found: C,49.38; H,6.62; N, 8.68.

Part C: A solution of Part B material of example 7 (2.73 g, 0.01 moles)in THF (30 mL) was cooled to −78° C. and then added dropwise 1.6 Mn-BuLi in hexane (7.4 mL) over 15 mins. The mixture was stirred at −78°C. for 2½ h and then added a solution of 2,4-dichlorobenzoyl chloride in5.0 mL of THF over 15 mins. The mixture was stirred at −78° C. for 6 hand then warm to room temp and stirred overnight. The reaction mixturewas quenched with satd. NH₄Cl (50.0 ml), extracted with ethyl acetate(3*30 mL), washed with brine and stripped off the solvent in vacuum toafford orange yellow liquid (4.3 g). TLC (30:70 EtOAc/hexane) of thecrude showed absence of starting material spot (Rf=0.4) and a new spotat Rf=0.47. The crude was purified by flash column chromatography on asilica gel using 30% EtOAC/hexane to afford 2.4 g (mp 129-130° C., 59%yield) of benzoyl derivative as white solid. Mass spec. (CI-NH3): 411(M⁺). Anal. calcd. for C₂₀H₂₄N₂O₃Cl₂: C, 58.40; H, 5.88; N, 6.81. Found:C, 58.45; H, 5.95; N, 6.68.

Part D: A solution of part C material of example 7 (2.3 g, 0.056 moles)in acetone (60 mL) was cooled to 15° C. and then added 3M aq. HCl (120mL) over 15 mins. The mixture was stirred below 30° C. for 24 h. TLC(30:70 EtOAc/hexane) showed a new spot at Rf=0.58 along withdisappearance of starting material (Rf=0.43). The solvent was removedunder vacuum, extracted with ethyl acetate (3*50 mL), washed with brineand stripped off the solvent in vacuum to afford yellow liquid (2.4 g).The crude was purified by flash column chromatography on a silica gelusing dichloromethane as eluent to afford 1.46 g (71% yield) of ketoaldehyde derivative as yellow solid (mp 43-44° C.). Mass spec. (NH₃-CI):367 (M⁺). Anal. calcd. for C₁₈H₂₀N₂O₂Cl₂: C, 58.87; H, 5.50; N,7.64.Found: C,58.96; H,5.34; N,7.46.

Part E: A mixture of Part D material of example 7(1.0 g, 0.0027 moles)in methanol (50 mL) was treated with NaCN (Aldrich, 0.67 g, 0.0136moles, 5 equiv.), AcOH (Baker, 260 mg; 0.00432 moles, 1.6 equiv.) andMnO₂, activated (Aldrich, 3.34 g, 0.057 moles, 21 equiv.). The resultingmixture was stirred at room temp under nitrogen for 20 h. TLC (30:70EtOAc/hexane) revealed absence of starting material at Rf=0.58 andshowed a new spot at Rf=0.4. The reaction mixture was filtered throughcelite, washed with methanol, concentrated in vacuo. The residue wasdiluted with water, extracted with ethyl acetate, washed with brine,dried and concentrated in vacuo to afford 0.98 g of yellow oil. Thecrude was purified by flash column chromatography on a silica gel using30:70 EtOAc/hexane as eluent to afford 910 mg (85%) of keto esterderivative as yellow oil. Mass spec.: 397.2 (M⁺). Anal. calcd. forC₁₉H₂₂N₂O₃Cl₂: C,57.44; H,5.58; N,7.05. Found: C, 57.25; H, 5.70; N,6.80.

Part F: Title Compound: A mixture of Part E material of example 7 (0.100g, 0.00025 moles) in ethylene glycol (2 mL) was treated with anhydrousmethylhydrazine (0.105 g, 0.0033 moles) and refluxed under nitrogen for4 h. TLC (30:70 EtOAc/hexane) revealed a new spot (Rf=0.44) along withdisappearance of starting material (Rf=0.4. The reaction mixture wascooled to room temp and poured over 25 mL of water, extracted with EtOAc(3*15 mL), washed with brine and dried. The solvent was removed undervacuo and purified the crude by flash column chromatography on a silicagel using 15% EtOAc/hexane to afford colorless oil which wascrystallized from hexane to afford 42 mg of white solid (43%, mp 89-90°C.). Mass spec. (CI-NH₃): 393.2 (M⁺). Anal. calcd. for C₁₉H₂₂N₄Cl₂O: C,58.02; H, 5.65; N, 14.24. Found: C,58.32; H, 5.59; N, 14.14.

Example 8(±)-4-(2,4-dichlorophenyl)-2-ethyl-1-(1-methyl)butyl-imidazo[4,5-d]pyridazin-7-one

A mixture of Part E material of example 7 (0.460 g, 0.00115 moles) inethylene glycol (5 mL) was treated with anhydrous hydrazine (0.48 g,0.0151 moles) and refluxed under nitrogen for 4 h. TLC (30:70EtOAc/hexane) revealed a new spot (Rf=0.44) along with disappearance ofstarting material (Rf=0.4). The reaction mixture was cooled to room tempand poured over 25 mL of water, extracted with EtOAc (3*15 mL), washedwith brine and dried. The solvent was removed under vacuo and purifiedthe crude by flash-column chromatography on a silica gel using 15%EtOAc/hexane to afford colorless oil which was crystallized from hexaneto afford 310 mg of white solid (71%, mp 217-18° C.). Mass spec.(CI-NH₃):379.2 (M⁺). Anal. calcd. for C₁₈H₂₀N₄Cl₂O: C, 57.00; H,5.33;N,14.77. Found: C,57.02; H, 5.35; N, 14.59.

Example 9(±)-4-(2,5-dimethyl-4-methoxyphenyl)-2-ethyl-6-(N-methyl)-1-(1-methyl)butyl-imidazo[4,5-d]pyridazin-7-one

Part A: Synthesis of 2,5-dimethyl-4-methoxybenzoyl chloride: To astirred mixture of 2,5-dimethyl-4-methoxybenzaldehyde (6.7 g, 0.004moles) in acetone (140 mL) at 60° C. was added KMnO₄ (8.46 g, 0.0054moles) dissolved in water (250 mL) dropwise over 30 mins. The reactionmixture quickly turned into brown suspended solution. The reactionmixture was further continued for 1 h. The reaction mixture was cooledto room temp., filtered through celite and extracted with diethyl ether.The aq. layer was acidified with con. HCl, filtered the white solidseparated, washed with water and dried at 50° C. for 30 mins undervacuum to afford 3.46 g of carboxylic acid as white solid (mp 161-162°C., 48% yield). The carboxylic acid (3.4 g, 0.0189 moles) was dissolvedin 75 mL of anhydrous benzene and added few drops of pyridine followedby addition of thionyl chloride (5.0 mL, 0.0689, 3.65 equiv., fw 118.97,d 1.631). The resultant mixture was refluxed at reflux for 20 h. Thesolvent was removed under vacuum, the solid thus resulted was treatedwith 5.0 mL of hexane and filtered the undissolved white solid (3.7 g,mp 84-85° C., 98.7%).

Part B: A solution of part B material of example 7 (2.73 g, 0.01 moles)in THF was cooled to −78° C. and then added dropwise 1.6 M n-BuLi inhexane (7.4 mL, 0.0115 moles) over 15 mins. The mixture was stirred at−78° C. for 2½ h and then added a solution of 2,5-(Me)₂-4-OMe—Ph—COCl(2.2 g, 0.012 moles) in 10.0 mL of THF over 15 mins. The mixture wasstirred at −78° C. for 6 h and then warm to room temp and stirredovernight. The reaction mixture was quenched with satd. NH₄Cl (50.0 ml),extracted with ethyl acetate (3*30 mL), washed with brine and strippedoff the solvent in vacuum to afford orange yellow liquid. TLC (30:70EtOAc/hexane) of the crude showed absence of starting material spot(Rf=0.4) along with product spot appeared at Rf=0.38. The crude waspurified by flash column chromatography on a silica gel using 15%EtOAC/hexane to afford 1.53 g (mp 160-162° C., 38% yield) of desiredbenzoyl derivative as pale yellow solid. Mass spec. (CI-NH₃): 401.3(M+H). Anal. calcd. for C₂₃H₃₂N₂O₄: C, 68.97; H, 8.05; N, 6.99. Found;C, 69.05; H, 8.10; N, 6.33.

Part C: A solution of part B material of example 9 (1.4 g, 0.0035 moles)in acetone (30 mL) was cooled to 15° C. and then added 3M aq. HCl (60mL) over 15 mins. The mixture was stirred below 30° C. for 24 h. TLC(30:70 EtOAc/hexane) showed product spot at 0.56. The solvent wasremoved under vacuum, extracted with ethyl acetate (3*50 mL), washedwith brine and stripped off the solvent in vacuum to afford yellowliquid. The crude was purified by flash column chromatography on asilica gel using dichloromethane, followed by 1% MeOH/dichloromethane aseluents to afford 0.48 g (39% yield) of desired product as yellowliquid. HRMS calcd. for C₂₁H₂₉N₂O₃:357.2178. Found:357.2169 (M+H)

Part D: A mixture of part C material of example 9 (0.357 g, 1.0 mmole)in methanol (30 mL) was treated with NaCN (Aldrich, 0.245 g, 5.0 Mmoles,5 equiv.), AcOH (Baker, 96 mg; 1.6 mmoles, 1.6 equiv.) and MnO₂,activated (Aldrich, 1.24 g, 21.0 mmoles, 21 equiv.). The resultingmixture was stirred at room temp under nitrogen for 24 h. TLC (30:70EtOAc/hexane) revealed absence of starting material at Rf=0.56 andshowed a new spot at Rf=0.30. The reaction mixture was filtered throughcelite, washed with methanol, concentrated in vacuo. The residue wasdiluted with water, extracted with ethyl acetate, washed with brine,dried and concentrated in vacuo to afford yellow oil. The crude waspurified by flash column chromatography on a silica gel using 30:70EtOAc/hexane as eluent to afford 205 mg (53%) of ketoester derivative aspale yellow oil. HRMS calcd. for C₂₂H₃₀N₂O₄: 386.2205. Found: 387.2264(M+H).

Part E: A mixture of part D material of example 9 (0.100 g, 0.000259moles) in ethylene glycol (3.0 mL) was treated with anhydrousmethylhydrazine (0.15 g, Aldrich, 0.0033 moles, 13 equiv.) and refluxedunder nitrogen for 14 h. TLC (30:70 EtOAc/hexane) revealed a new spot(Rf=0.40) along with disappearance of starting material (Rf=0.3). Thereaction mixture was cooled to room temp and poured over 25 mL of water,extracted with EtOAc (3*15 mL), washed with brine and dried. The solventwas removed under vacuo and purified the crude by flash columnchromatography on a silica gel using 30% EtOAc/hexane to afford 43 mg(43% yield) of a solid: HRMS calcd. for C₂₂H₃₁N₄O₂: 383.2447. Found:383.2433 (M+H).

Using the above procedures and modifications known to one skilled in theart of organic synthesis, the following additional examples of Tables1-4 may be prepared.

The examples delineated in Tables 1, 2, 3 and 4 may be prepared by themethods outlined in Examples 1, 2 or 3 or combinations thereof. Commonlyused abbreviations are: Ph is phenyl, Pr is propyl, Me is methyl, Et isethyl, Bu is butyl, Ex is Example, amorph. is amorphous.

Example 5444-(2,4-Dichlorophenyl)-2-ethyl-6-(N-methyl)-imidazo[4,5-d]pyridazin-7-one

Part A: Synthesis of 1-[(Benzyloxy)methyl]4,5-dibromo-2-ethylimidazole:To a mechanically stirred solution of 4,5-dibromo-2-ethylimidazole (25.4g, 0.1 mole,) in anhydrous DMF (250 mL) was treated with K₂CO₃ (69.1 g,fw=138.2, 0.5 moles, 5 equiv.) followed by dropwise addition of benzylchloromethyl ether (18.5 g, 0.11 moles, 93% pure, TCI, fw=156.61) andstirred overnight at room temp under nitrogen for 20 h. TLC (30:70EtOAc/hexane) revealed absence of starting material imidazole (Rf=0.2)along with formation of product (Rf=0.71). The reaction mixture wasfiltered, washed the solid with dichloromethane and the combinedfilterate was evaporated under reduced pressure and purified the crude(47 g) by flash column chromatography (dichloromethane eluent) to afford31.75 g (85%) of colorless oil. Mass spectrum (m/z=375, M+H).

Part B: Synthesis of1-[(Benzyloxy)methyl]-4-bromo-2-ethyl-5-formylimidazole: A solution of1-[(Benzyloxy)methyl]-4,5-dibromo-2-ethylimidazole (28.0 g, 75.0 mmol,Part A of example 544) in THF (300 mL) was cooled to −78° C. undernitrogen atmosphere and then added dropwise 1.6 M n-BuLi in hexane(51.75 mL, 82.5 mmol, Aldrich) over 30 mins. The mixture was stirred at−78° C. for 30 mins and then added DMF (16.5 g, 225 mmol, Aldrich)dropwise over 15 mins. The mixture was stirred at −78° C. for 30 mins. Asmall portion of the reaction mixture was quenched with satd. NH₄Cl at−78° C. TLC (30:70 EtOAc/hexane) revealed both starting material andproduct showed almost identical Rf values (0.71 & 0.70) along withanother minor spot at Rf=0.15. However, mass spectrum (CI-NH₃) revealedabsence of starting material and formation of product (m/z=325, M+2H).The reaction mixture was quenched with satd. ammonium chloride (20 mL)at −78° C. and brought to room temp. The reaction mixture was extractedwith ethyl acetate (3×100 mL), washed with brine and dried withanhydrous MgSO₄. The solvent was evaporated under reduced pressure toafford crude yellow oil. The crude was purified by flah columnchromatography on a silica gel using dichloromethane as eluent to afford22.6 g (93%) of colorless oil. HRMS calcd. for C₁₄H₁₆N₂O₂Br: 323.0395.Found:323.0394 (M+H).

Part C: 1-[(Benzyloxy)methyl]-4-bromo-2-ethyl-5-formylimidazole ethyleneacetal: A mixture of1-[(Benzyloxy)methyl]-4-bromo-2-ethyl-5-formyl-imidazole (22.6 g, 0.0699moles) in benzene (400 mL) was treated with ethylene glycol (16.9 g,0.273 moles, fw 62, 3.9 equiv.), pyridine (2.76 g, 0.03495 moles,fw=79.1, 0.5 equiv.) and p-toluenesulfonic acid monohydrate (6.6 g,0.03495 moles, fw=190, 0.5 equiv). The reaction mixture was heated atreflux in a 20 mL capacity Dean-Stark trap equipped apparatus for 24hours. TLC (30:70 EtOAc/hexane) revealed a new spot at Rf=0.35 (visibleunder iodine) along with disappearance of starting material (Rf=0.70).The reaction mixture was cooled to room temperature, diluted with EtOAc(100 mL), washed with 10% sodium bicarbonate, brine and dried (MgSO₄).The solvent was evaporated under reduced pressure to furnish yellow oil.The crude was purified by flash column chromatography on silica gelusing 25% ethyl acetate/hexane mixture to afford 22.8 g (89%) colorlessoil. ¹H NMR (CDCl₃): 1.29-1.33 (t, 3H, CH₃), 2.71-2.78 (q, 2H, CH₂),3.96 (s, 4H, 2×OCH₂), 4.55 (s, 2H, CH₂), 5.4 (S, 2H, CH₂), 5.88 (S, 1H,CH), 7.27-7.38 (M, 5H, aromatic). HRMS calcd. for C_(l6)H₂₀N₂O₃Br₁:367.0658. Found: 367.0653 (M+H).

Part D:1-[(Benzyloxy)methyl]-4-(2,4-dichlorobenzoyl)-2-ethyl-5-formylimidazoleethylene acetal: A solution of1-[(Benzyloxy)methyl]-4-bromo-2-ethyl-5-formyl-imidazole ethylene acetal(22.5 g, 0.0613 moles, fw=367.25, Part C of Example 544) in THF (200.0mL) was cooled to −78° C. and then added dropwise 1.6 M n-BuLi in hexane(43.7 mL, 0.071 moles, 1.1 equiv.) over 15 mins under nitrogenatmosphere. The mixture was stirred at −78° C. for 90 mins and thenadded a solution of 2,4-dichlorobenzoyl chloride (14.3 g, 0.071 moles,1.1 equiv.) in THF (5.0 mL) over 15 mins. The mixture was stirred at−78° C. for 4 h followed by room temperature overnight. TLC (30:70EtOAc/hexane) showed a new spot at Rf=0.38 along with disappearance ofstarting material (Rf=0.35). The mixture was quenched with saturatedNH₄Cl (100.0 ml), extracted with ethyl acetate (3×150 mL), washed withbrine and dried (MgSO₄). The solvent was stripped off in vacuo to affordcrude product (yellow oil) which was purified by flash columnchromatography on a silica gel using 20% EtOAC/hexane to afford 12.3 g(mp 95-96° C., 43% yield) of desired product as white solid. ¹H NMR(CDCl₃): 1.22-1.27 (t, 3H, CH₃), 2.74-2.81 (q, 2H, CH₂), 3.94-4.03 (m,4H, 2×OCH₂), 4.59 (s, 2H, CH₂), 5.54 (s, 2H, CH₂), 6.62 (s, 1H, CH),7.27-7.54 (m, 8H, aromatic). Mass spectrum (CI-NH₃): 461 (M⁺). Anal.calcd. for C₂₃H₂₂N₂O₄Cl₂: C, 59.88; H, 4.82; N. 6.07. Found: C, 59.77;H, 4.78; N, 5.93.

Part E:1-[(Benzyloxy)methyl]-4-(2,4-dichlorobenzoyl)-2-ethyl-5-formylimidazole:The above acetal (12.1 g, 0.0263 moles, Part D of Example 544) wasdissolved in acetone (200.0 mL) and treated with 3.0 M aqeous HCl (400.0mL) at room temperature. The reaction mixture was stirred for 24 h atthis temperature and TLC (30:70 EtOAc/hexane) showed a new spot atRf=0.55. It was then quenched with saturated NaCl (50.0 ml), extractedwith ethyl acetate (3×150 mL), washed with brine and dried (MgSO₄). Thesolvent was removed in vacuum to afford yellow liquid and purified thecrude by flash column chromatography on a silica gel using 15%EtOAC/hexane to afford 6.0 g (55% yield) of desired product as colorlessoil. ¹H NMR (CDCl₃): 1.27-1.32 (t, 3H, CH₃), 2.78-2.86 (q, 2H, CH₂),4.62 (s, 2H, CH₂), 5.92 (s, 2H, CH₂), 7.25-7.55 (m, 8H, aromatic), 10.39(s, 1H, CHO). Mass spectrum (CI-NH₃): 417 (M⁺) Anal. calcd. forC₂₁H₁₈N₂O₃Cl₂: C, 60.44; H, 4.36; N, 6.71. Found: C, 60.43; H, 4.45; N,6.49.

Part F: Methyl1-[(Benzyloxy)methyl]-4-(2,4-dichlorobenzoyl)-2-ethyl-5-imidazolecarboxylate: A mixture of 2-Et-5-CHO-imidazole derivative (6.0 g,fw=417, 14.34 mmoles, Part E of Example 544) in methanol (120 mL) wastreated with NaCN (Aldrich, fw=49, 3.54 g, 12.0 mmoles, 5 equiv.), AcOH(Baker, fw=60, 1.38 g; 22.92 mmoles, 1.6 equiv.) and MnO₂, activated(Aldrich, fw=86.94, 25.8 g, 301.2 mmoles, 21 equiv.). The resultingmixture was stirred at room temp under nitrogen for 3 h. TLC (30:70EtOAc/hexane) revealed absence of starting material at Rf=0.55 andshowed a new spot at Rf=0.35. The reaction mixture was filtered throughcelite, washed with methanol, concentrated in vacuo. The residue wasdiluted with water, extracted with ethyl acetate, washed with brine,dried and concentrated in vacuo to afford yellow oil. The crude waspurified by flash column chromatography on a silica gel using 30:70EtOAc/hexane as eluent to afford 4.62 g (72% yield) of colorless oil.HRMS calcd. for C₂₂H₂₁Cl₂N₂O₄: 447.0878. Found: 447.0870 (M+H). Anal.calcd. for C₂₂H₂₀Cl₂N₂O₄: C, 59.07; H, 4.52; N, 6.26. Found: C, 58.97;H, 4.65; N, 6.07

Part G:1-[(Benzyloxy)methyl]-4-(2,4-dichlorophenyl)-2-ethyl-imidazo[4,5-d]pyridazin-7-one:A mixture of imidazole deriv. (3.55 g, fw=447, 0.00794 moles, Part F ofExample 544) in ethanol (50 mL) was treated with anhydrous hydrazine(3.3 g, 0.102 moles, 13 equiv) and refluxed under nitrogen for 2 h. TLC(30:70 EtOAc/hexane) revealed absence of starting material (Rf=0.35) andshowed a new spot (Rf=0.27). The solvent was removed under vacuo andpurified the crude titurating with 1:1 EtOH/hexane to afford 2.2 g (65%yield, mp 174-175° C.) of desired product as white solid. Mass spectrum(APcI): (m/z=429, M⁺). Anal. calcd. for C₂₁H₁₈N₄Cl₂O₂: C, 58.75; H,4.24; N, 13.05. Found: C, 58.65; H, 4.30; N, 12.86.

Part H:1-[(Benzyloxy)methyl]-4-(2,4-dichlorophenyl)-2-ethyl-6-(N-methyl)-imidazo[4,5-d]pyridazin-7-one:To a solution of the above 6H-imidazo[4,5-d]pyridazin-7-one derivative(2.2 g, 0.005 moles, Part G of Example 544) in benzene (100 mL) wasadded powdered KOH (0.43 g, 0.0076 moles), n-Bu₄NBr (161 mg, 0.0005moles ) and MeI (excess) at room temperature. The reaction mixtureappeared white suspension and stirred for 48 h. TLC (30:70 EtOAc/hexane)showed a new spot at Rf=0.40 along with disappearance of startingmaterial (Rf=0.27). The reaction mixture was diluted with EtOAc (50 mL),washed with brine (10 mL), dried with MgSO₄ and concentrated to aresidue. The crude was purified by flash column chromatography on asilica gel using 25:75 EtOAc/hexane as eluent to afford 1.96 g (86%yield, mp 80-81° C.) of the product as white solid. Anal. calcd. forC₂₃H₂₀N₄Cl₂O₂: C, 59.60; H, 4.56; N, 12.64. Found: C, 59.61; H, 4.57; N,12.52.

Part I: Title Compound: A mixture of1-[(Benzyloxy)methyl]-4-(2,4-dichlorophenyl)-2-ethyl-6-(N-methyl)-imidazo[4,5-d]pyridazin-7-one(2.6 g, fw=443.33, 5.87 mmol, Part H of Example 544) in ethanol (100 mL)was treated with conc. HCl (2.93 mL, 29.3 mmol, 5.0 equiv) and refluxedunder nitrogen for 60 mins. TLC (30:70 EtOAc/hexane) revealeddisappearance of starting material (Rf=0.40) and a new spot appearednear the origin. The reaction mixture was cooled to room temperatureadjusted the pH using NaHCO₃ and the solvent was removed under vacuo andpurified the crude by flash column chromatography on a silica gel using50% EtOAc/hexane to afford 1.85 g (mp 234-235° C., 97% yield) of desiredproduct as white solid. NMR (CDCl₃): 1.46-1.52 (t, 3H, CH₃), 3.04-3.11(q, 2H, CH₂), 4.04 (s, 3H, N-Me), 7.38-7.41 (d, 2H, aromatic), 7.54-7.57(m, 3H, aromatic), 13.65 (bs, 1H, NH). Mass spectrum (CI-NH₃): m/z=323(M⁺). HRMS calcd. for C₁₄H₁₃N₄Cl₂O₁: 323.0466. Found:323.0477 (M+H).Anal. calcd. for C₁₄H₁₂N₄Cl₂O₁: C, 52.03; H, 3.74. Found: C, 51.92 ; H,4.07.

Example 5461-Butyl-4-(2,4-dichlorophenyl)-2-ethyl-6-(N-methyl)-imidazo[4,5-d]pyridazin-7-one

To a solution of imidazopyridazin-7-one deriv. (32.3 mg, fw=323, 0.1mmol, Part I of example 544) in DMF (2.0 mL) under nitrogen atmospherewas added 60% NaH in oil dispersion (6.0 mg, fw=24, 0.15 mmol, 1.5equiv.). The mixture was stirred at room temp for 5 mins and then added1-bromobutane (27.6 mg, fw=184, 0.15 mmol, 1.5 equiv) to reactionmixture and stirred overnight. TLC (30:70 EtOAc/hexane) showed a newspot at Rf=0.36 along with disappearance of starting material(Rf=origin). The reaction mixture was diluted with water (5.0 mL),extracted with EtOAc (3*5 mL), washed with brine (10 mL), dried withMgSO₄ and concentrated to a residue. The crude was purified by flashcolumn chromatography on a silica gel using 25:75 EtOAc/hexane as eluentto afford 29.7 mg (78% yield) of the product as colorless oil. HRMScalcd. for C₁₈H₂₁N₄O₁Cl₂: 379.1092. Found: 379.1086 (M+H)

Example 5484-(2,4-dichlorophenyl)-2-ethyl-1-[1-(ethyl)pentyl)]-6-(N-methyl)-imidazo[4,5-d]pyridazin-7-one

To a solution of imidazopyridazin-7-one deriv. (48.3 mg, fw=323, 0.15mmol, Part I of Example 544) in THF (2.0 mL) under nitrogen atmospherewas added PPh₃ (43.3 mg, fw=262.29, 0.165 mmol, 1.1 equiv.), and3-heptanol (21.0 mg, Aldrich, 0.18 mmol, fw=116.2, 1.2 equiv.). Themixture was cooled to −20° C. and then added diisopropylazodicarboxylate(33.3 microlit., Aldrich, 0.165 mmol, fw=202, 1.1 equiv.) dropwise usinga syringe. The resultant mixture was stirred at −20° C. for 2 h followedby room temperature for 20 h. TLC (30:70 EtOAc/hexane) showed a new spotat Rf=0.53 along with trace amount of starting material (Rf=origin). Thereaction mixture was concentrated to a residue. The crude was purifiedby flash column chromatography on a silica gel using 15:85 EtOAc/hexaneas eluent to afford 37 mg (58% yield, 110-111° C.) of the product aswhite solid. HRMS calcd. for C₂₁H₂₇N₄O₁Cl₂: 421.1562. Found:421.1555(M+H).

TABLE 1

Ex. R₃ R₂ Ar mp (° C.) 2 Me 3-pentyl 2,4-Cl₂—Ph 94-95 3 Et 3-pentyl214-Cl₂—Ph oil 4 Pr 3-pentyl 2,4-Cl₂—Ph oil 5 CH₂-c-C₃H₅ 3-pentyl2,4-Cl₂—Ph oil 6 Me 3-pentyl 2,4-(CF₃)₂—Ph 139-140 7 Me 2-pentyl2,4-Cl₂—Ph 89-90 9 Me 2-pentyl 2,5-(Me)₂-4-MeO-Ph amorph. 10 MeCH(Et)CH₂OH 2,4-Cl₂—Ph 12 Me CH(Et)CH₂OMe 2,4-Cl₂—Ph 13 MeCH(Et)CH₂CH₂OMe 2,4-Cl₂—Ph 14 Me 2-butyl 2,4-Cl₂—Ph 15 Me cyclobutyl2,4-Cl₂—Ph oil 16 Me cyclopentyl 2,4-Cl₂—Ph 180-181 17 MeCH(Me)cyclobutyl 2,4-Cl₂—Ph 18 Me CH(Me)cyclopropyl 2,4-Cl₂—Ph oil 19 MeCH(Et)cyclobutyl 2,4-Cl₂—Ph 20 Me CH(Et)cyclopropyl 2,4-Cl₂—Ph 117-11821 Me CH(Me)CH₂-cyclobutyl 2,4-Cl₂—Ph 22 Me CH(OH)CH₂-cyclobutyl2,4-Cl₂—Ph 23 Me CH(Me)CH₂-cyclopropyl 2,4-Cl₂—Ph 24 MeCH(Et)CH₂-cyclobutyl 2,4-Cl₂—Ph 25 Me CH(Et)CH₂-cyclopropyl 2,4-Cl₂—Ph26 Me CH(CH₂OMe)cyclobutyl 2,4-Cl₂—Ph 27 Me CH(CH₂OMe)cyclopropyl2,4-Cl₂—Ph 28 Me CH(CH₂OEt)cyclobutyl 2,4-Cl₂—Ph 29 MeCH(CH₂OEt)cyclopropyl 2,4-Cl₂—Ph 30 Me CH(cyclobutyl)₂ 2,4-Cl₂—Ph 31 MeCH(cyclopropyl)₂ 2,4-Cl₂—Ph 140-142 32 Me CH(Et)CH₂CONMe₂ 2,4-Cl₂—Ph 33Me CH(Et)CH₂CH₂NMe₂ 2,4-Cl₂—Ph 34 Me CH(CH₂OMe)Me 2,4-Cl₂—Ph 35 MeCH(CH₂OMe)Et 2,4-Cl₂—Ph 36 Me CH(CH₂OMe)Pr 2,4-Cl₂—Ph 37 Me CH(CH₂OEt)Me2,4-Cl₂—Ph 38 Me CH(CH₂OEt)Et 2,4-Cl₂—Ph 39 Me CH(CH₂OEt)Pr 2,4-Cl₂—Ph40 Me CH(CH₂C≡CMe)Et 2,4-Cl₂—Ph 41 Me CH(CH₂CH═CHMe)Et 2,4-Cl₂—Ph 42 MeCH(Et)CH₂OH 2,4,6-Me₃-Ph 43 Me CH(Et)CH₂OMe 2,4,6-Me₃-Ph 44 MeCH(Et)CH₂CH₂OMe 2,4,6-Me₃-Ph 45 Me 3-pentyl 2,4,6-Me₃-Ph 46 Me 2-pentyl2,4,6-Me₃-Ph 47 Me 2-butyl 2,4,6-Me₃-Ph 48 Me cyclobutyl 2,4,6-Me₃-Ph 49Me cyclopentyl 2,4,6-Me₃-Ph 50 Me CH(Me)cyclobutyl 2,4,6-Me₃-Ph 51 MeCH(Me)cyclopropyl 2,4,6-Me₃-Ph 52 Me CH(OMe)cyclopropyl 2,4,6-Me₃-Ph 53Me CH(Et)cyclobutyl 2,4,6-Me₃-Ph 54 Me CH(Et)cyclopropyl 2,4,6-Me₃-Ph ssMe CH(Me)CH₂-cyclobutyl 2,4,6-Me₃-Ph 56 Me CH(Me)CH₂-cyclopropyl2,4,6-Me₃-Ph 57 Me CH(OMe)CH₂-cyclopropyl 2,4,6-Me₃-Ph 58 MeCH(Et)CH₂-cyclobutyl 2,4,6-Me₃-Ph 59 Me CH(Et)CH₂-cyclopropyl2,4,6-Me₃-Ph 60 Me CH(CH₂OMe)cyclobutyl 2,4,6-Me₃-Ph 61 MeCH(CH₂OMe)cyclopropyl 2,4,6-Me₃-Ph 62 Me CH(CH₂OEt)cyclobutyl2,4,6-Me₃-Ph 63 Me CH(CH₂OEt)cyclopropyl 2,4,6-Me₃-Ph 64 MeCH(cyclobutyl)₂ 2,4,6-Me₃-Ph 65 Me CH(cyclopropyl)₂ 2,4,6-Me₃-Ph 66 MeCH(Et)CH₂CONMe₂ 2,4,6-Me₃-Ph 67 Me CH(Et)CH₂CH₂NMe₂ 2,4,6-Me₃-Ph 68 MeCH(CH₂OMe)Me 2,4,6-Me₃-Ph 69 Me CH(CH₂OMe)Et 2,4,6-Me₃-Ph 70 MeCH(CH₂OMe)Pr 2,4,6-Me₃-Ph 71 Me CH(CH₂OEt)Me 2,4,6-Me₃-Ph 72 MeCH(CH₂OEt)Et 2,4,6-Me₃-Ph 73 Me CH(CH₂OEt)Pr 2,4,6-Me₃-Ph 74 MeCH(CH₂C≡CMe)Et 2,4,6-Me₃-Ph 75 Me CH(CH₂CH═CHMe)Et 2,4,6-Me₃-Ph 76 MeCH(Et)CH₂OH 2,4-Me₂-Ph 77 Me CH(Et)CH₂OMe 2,4-Me₂-Ph 78 MeCH(Et)CH₂CH₂OMe 2,4-Me₂-Ph 79 Me 3-pentyl 2,4-Me₂-Ph 80 Me 2-pentyl2,4-Me₂-Ph 81 Me 2-butyl 2,4-Me₂-Ph 82 Me cyclobutyl 2,4-Me₂-Ph 83 Mecyclopentyl 2,4-Me₂-Ph 84 Me CH(Me)cyclobutyl 2,4-Me₂-Ph 85 MeCH(OH)cyclobutyl 2,4-Me₂-Ph 86 Me CH(Me)cyclopropyl 2,4-Me₂-Ph 87 MeCH(OH)cyclopropyl 2,4-Me₂-Ph 88 Me CH(Et)cyclobutyl 2,4-Me₂-Ph 89 MeCH(Et)cyclopropyl 2,4-Me₂-Ph 90 Me CH(Me)CH₂-cyclobutyl 2,4-Me₂-Ph 91 MeCH(Me)CH₂-cyclopropyl 2,4-Me₂-Ph 92 Me CH(OMe)CH₂-cyclopropyl 2,4-Me₂-Ph93 Me CH(Et)CH₂-cyclobutyl 2,4-Me₂-Ph 94 Me CH(Et)CH₂-cyclopropyl2,4-Me₂-Ph 9s Me CH(CH₂OMe)cyclobutyl 2,4-Me₂-Ph 96 MeCH(CH₂OMe)cyclopropyl 2,4-Me₂-Ph 97 Me CH(CH₂OEt)cyclobutyl 2,4-Me₂-Ph98 Me CH(CH₂OEt)cyclopropyl 2,4-Me₂-Ph 99 Me CH(cyclobutyl)₂ 2,4-Me₂-Ph100 Me CH(cyclopropyl)₂ 2,4-Me₂-Ph 101 Me CH(Et)CH₂CONMe₂ 2,4-Me₂-Ph 102Me CH(Et)CH₂CH₂NMe₂ 2,4-Me₂-Ph 103 Me CH(CH₂OMe)Me 2,4-Me₂-Ph 104 MeCH(CH₂OMe)Et 2,4-Me₂-Ph 105 Me CH(CH₂OMe)Pr 2,4-Me₂-Ph 106 MeCH(CH₂OEt)Me 2,4-Me₂-Ph 107 Me CH(CH₂OEt)Et 2,4-Me₂-Ph 108 MeCH(CH₂OEt)Pr 2,4-Me₂-Ph 109 Me CH(CH₂C≡CMe)Et 2,4-Me₂-Ph 110 MeCH(CH₂C≡CMe)Et 2,4-Me₂-Ph 111 Me CH(Et)CH₂OH 2-Me-4-MeO—Ph 112 MeCH(Et)CH₂OMe 2-Me-4-MeO—Ph 113 Me CH(Et)CH₂CH₂OMe 2-Me-4-MeO—Ph 114 Me3-pentyl 2-Me-4-MeO—Ph 125-126 115 Me 2-pentyl 2-Me-4-MeO—Ph oil 116 Me2-butyl 2-Me-4-MeO—Ph 117 Me cyclobutyl 2-Me-4-MeO—Ph 118 Me cyclopentyl2-Me-4-MeO—Ph 119 Me CH(Me)cyclobutyl 2-Me-4-MeO—Ph 120 MeCH(Me)cyclopropyl 2-Me-4-MeO—Ph 121 Me CH(Et)cyclobutyl 2-Me-4-MeO—Ph122 Me CH(Et)cyclopropyl 2-Me-4-MeO—Ph 123 Me CH(Me)CH₂-cyclobutyl2-Me-4-MeO—Ph 124 Me CH(Me)CH₂-cyclopropyl 2-Me-4-MeO—Ph 125 MeCH(Et)CH₂-cyclobutyl 2-Me-4-MeO—Ph 126 Me CH(Et)CH₂-cyclopropyl2-Me-4-MeO—Ph 127 Me CH(CH₂OMe)cyclobutyl 2-Me-4-MeO—Ph 128 MeCH(CH₂OMe)cyclopropyl 2-Me-4-MeO—Ph 129 Me CH(CH₂OEt)cyclobutyl2-Me-4-MeO—Ph 130 Me CH(CH₂OEt)cyclopropyl 2-Me-4-MeO—Ph 131 MeCH(cyclobutyl)₂ 2-Me-4-MeO—Ph 132 Me CH(cyclopropyl)₂ 2-Me-4-MeO—Ph 133Me CH(Et)CH₂CONMe₂ 2-Me-4-MeO—Ph 134 Me CH(Et)CH₂CH₂NMe₂ 2-Me-4-MeO—Ph135 Me CH(CH₂OMe)Me 2-Me-4-MeO—Ph 136 Me CH(CH₂OMe)Et 2-Me-4-MeO—Ph 137Me CH(CH₂OMe)Pr 2-Me-4-MeO—Ph 138 Me CH(CH₂OEt)Me 2-Me-4-MeO—Ph 139 MeCH(CH₂OEt)Et 2-Me-4-MeO—Ph 140 Me CH(CH₂OEt)Pr 2-Me-4-MeO—Ph 141 MeCH(CH₂C≡CMe)Et 2-Me-4-MeO—Ph 142 Me CH(CH₂CH═CHMe)Et 2-Me-4-MeO—Ph 143Me CH(Et)CH₂OH 2-Cl-4-MeO—Ph 144 Me CH(Et)CH₂OMe 2-Cl-4-MeO—Ph 145 MeCH(Et)CH₂CH₂OMe 2-Cl-4-MeO—Ph 146 Me 3-pentyl 2-Cl-4-MeO—Ph 147 Me2-pentyl 2-Cl-4-MeO—Ph 112-113 148 Me 2-butyl 2-Cl-4-MeO—Ph 149 Mecyclobutyl 2-Cl-4-MeO—Ph 150 Me cyclopentyl 2-Cl-4-MeO—Ph 151 MeCH(Me)cyclobutyl 2-Cl-4-MeO—Ph 152 Me CH(Me)cyclopropyl 2-Cl-4-MeO—Ph153 Me CH(Et)cyclobutyl 2-Cl-4-MeO—Ph 154 Me CH(Et)cyclopropyl2-Cl-4-MeO—Ph 155 Me CH(Me)CH₂-cyclobutyl 2-Cl-4-MeO—Ph 156 MeCH(Me)CH₂-cyclopropyl 2-Cl-4-MeO—Ph 157 Me CH(Et)CH₂-cyclobutyl2-Cl-4-MeO—Ph 158 Me CH(Et)CH₂-cyclopropyl 2-Cl-4-MeO—Ph 159 MeCH(CH₂OMe)cyclobutyl 2-Cl-4-MeO—Ph 160 Me CH(CH₂OMe)cyclopropyl2-Cl-4-MeO—Ph 161 Me CH(CH₂OEt)cyclobutyl 2-Cl-4-MeO—Ph 162 MeCH(CH₂OEt)cyclopropyl 2-Cl-4-MeO—Ph 163 Me CH(cyclobutyl)₂ 2-Cl-4-MeO—Ph164 Me CH(cyclopropyl)₂ 2-Cl-4-MeO—Ph 165 Me CH(Et)CH₂CONMe₂2-Cl-4-MeO—Ph 166 Me CH(Et)CH₂CH₂NMe₂ 2-Cl-4-MeO—Ph 167 Me CH(CH₂OMe)Me2-Cl-4-MeO—Ph 168 Me CH(CH₂ONe)Et 2-Cl-4-MeO—Ph 169 Me CH(CH₂OMe)Pr2-Cl-4-MeO—Ph 170 Me CH(CH₂OEt)Me 2-Cl-4-MeO—Ph 171 Me CH(CH₂OEt)Et2-Cl-4-MeO—Ph 172 Me CH(CH₂OEt)Pr 2-Cl-4-MeO—Ph 173 Me CH(CH₂C≡CMe)Et2-Cl-4-MeO—Ph 174 Me CH(CH₂CH═CHMe)Et 2-Cl-4-MeO—Ph 175 Me CH(Et)CH₂OH2-Cl-4,5-(MeO)₂-Ph 176 Me CH(Et)CH₂OMe 2-Cl-4,5-(MeO)₂-Ph 177 MeCH(Et)CH₂CH₂OMe 2-Cl-4,5-(MeO)₂-Ph 178 Me 3-pentyl 2-Cl-4,5-(MeO)₂-Ph179 Me 2-pentyl 2-Cl-4,5-(MeO)₂-Ph 180 Me 2-butyl 2-Cl-4,5-(MeO)₂-Ph 181Me cyclobutyl 2-Cl-4,5-(MeO)₂-Ph 182 Me cyclopentyl 2-Cl-4,5-(MeO)₂-Ph183 Me CH(Me)cyclobutyl 2-Cl-4,5-(MeO)₂-Ph 184 Me CH(Me)cyclopropyl2-Cl-4,5-(MeO)₂-Ph 185 Me CH(Et)cyclobutyl 2-Cl-4,5-(MeO)₂-Ph 186 MeCH(Et)cyclopropyl 2-Cl-4,5-(MeO)₂-Ph 187 Me CH(Me)CH₂-cyclobutyl2-Cl-4,5-(MeO)₂-Ph 188 Me CH(Me)CH₂-cyclopropyl 2-Cl-4,5-(MeO)₂-Ph 189Me CH(Et)CH₂-cyclobutyl 2-Cl-4,5-(MeO)₂-Ph 190 Me CH(Et)CH₂-cyclopropyl2-Cl-4,5-(MeO)₂-Ph 191 Me CH(CH₂OMe)cyclobutyl 2-Cl-4,5-(MeO)₂-Ph 192 MeCH(CH₂OMe)cyclopropyl 2-Cl-4,5-(MeO)₂-Ph 193 Me CH(CH₂OEt)cyclobutyl2-Cl-4,5-(MeO)₂-Ph 194 Me CH(CH₂OEt)cyclopropyl 2-Cl-4,5-(MeO)₂-Ph 195Me CH(cyclobutyl)₂ 2-Cl-4,5-(MeO)₂-Ph 196 Me CH(cyclopropyl)₂2-Cl-4,5-(MeO)₂-Ph 197 Me CH(Et)CH₂CONMe₂ 2-Cl-4,5-(MeO)₂-Ph 198 MeCH(Et)CH₂CH₂NMe₂ 2-Cl-4,5-(MeO)₂-Ph 199 Me CH(CH₂OMe)Me2-Cl-4,5-(MeO)₂-Ph 200 Me CH(CH₂OMe)Et 2-Cl-4,5-(MeO)₂-Ph 201 MeCH(CH₂OMe)Pr 2-Cl-4,5-(MeO)₂-Ph 202 Me CH(CH₂OEt)Me 2-Cl-4,5-(MeO)₂-Ph203 Me CH(CH₂OEt)Et 2-Cl-4,5-(MeO)₂-Ph 204 Me CH(CH₂OEt)Pr2-Cl-4,5-(MeO)₂-Ph 205 Me CH(CH₂C≡CMe)Et 2-Cl-4,5-(MeO)₂-Ph 206 MeCH(CH₂CH═CHMe)Et 2-Cl-4,5-(MeO)₂-Ph 207 Me CH(Et)CH₂OH 2-Cl-4-MeO-5-F—Ph208 Me CH(Et)CH₂OMe 2-Cl-4-MeO-5-F—Ph 209 Me CH(Et)CH₂CH₂OMe2-Cl-4-MeO-5-F—Ph 210 Me 3-pentyl 2-Cl-4-MeO-5-F—Ph 211 Me 2-pentyl2-Cl-4-MeO-5-F—Ph 212 Me 2-butyl 2-Cl-4-MeO-5-F—Ph 213 Me cyclobutyl2-Cl-4-MeO-5-F—Ph 214 Me cyclopentyl 2-Cl-4-MeO-5-F—Ph 215 MeCH(Me)cyclobutyl 2-Cl-4-MeO-5-F—Ph 216 Me CH(Me)cyclopropyl2-Cl-4-MeO-5-F—Ph 217 Me CH(Et)cyclobutyl 2-Cl-4-MeO-5-F—Ph 218 MeCH(Et)cyclopropyl 2-Cl-4-MeO-5-F—Ph 219 Me CH(OEt)cyclobutyl2-Cl-4-MeO-5-F—Ph 220 Me CH(Me)CH₂-cyclobutyl 2-Cl-4-MeO-5-F—Ph 221 MeCH(Me)CH₂-cyclopropyl 2-Cl-4-MeO-5-F—Ph 222 Me CH(Et)CH₂-cyclobutyl2-Cl-4-MeO-5-F—Ph 223 Me CH(Et)CH₂-cyclopropyl 2-Cl-4-MeO-5-F—Ph 224 MeCH(CH₂OMe)cyclobutyl 2-Cl-4-MeO-5-F—Ph 225 Me CH(CH₂OMe)cyclopropyl2-Cl-4-MeO-5-F—Ph 226 Me CH(CH₂OEt)cyclobutyl 2-Cl-4-MeO-5-F—Ph 227 MeCH(CH₂OEt)cyclopropyl 2-Cl-4-MeO-5-F—Ph 228 Me CH(cyclobutyl)₂2-Cl-4-MeO-5-F—Ph 229 Me CH(cyclopropyl)₂ 2-Cl-4-MeO-5-F—Ph 230 MeCH(Et)CH₂CONMe₂ 2-Cl-4-MeO-5-F—Ph 231 Me CH(Et)CH₂CH₂NMe₂2-Cl-4-MeO-5-F—Ph 232 Me CH(CH₂OMe)Me 2-Cl-4-MeO-5-F—Ph 233 MeCH(CH₂OMe)Et 2-Cl-4-MeO-5-F—Ph 234 Me CH(CH₂OMe)Pr 2-Cl-4-MeO-5-F—Ph 234Me CH(CH₂OEt)Me 2-Cl-4-MeO-5-F—Ph 235 Me CH(CH₂OEt)Et 2-Cl-4-MeO-5-F—Ph236 Me CH(CH₂OEt)Pr 2-Cl-4-MeO-5-F—Ph 237 Me CH(CH₂C≡CMe)Et2-Cl-4-MeO-5-F—Ph 238 Me CH(CH₂CH═CHMe)Et 2-Cl-4-MeO-5-F—Ph 239 MeCH(Et)CH₂OH 2-Me-4-MeO-5-F—Ph 240 Me CH(Et)CH₂OMe 2-Me-4-MeO-5-F—Ph 241Me CH(Et)CH₂CH₂OMe 2-Me-4-MeO-5-F—Ph 242 Me 3-pentyl 2-Me-4-MeO-5-F—Ph243 Me 2-pentyl 2-Me-4-MeO-5-F—Ph 244 Me 2-butyl 2-Me-4-MeO-5-F—Ph 245Me cyclobutyl 2-Me-4-MeO-5-F—Ph 246 Me cyclopentyl 2-Me-4-MeO-5-F—Ph 247Me CH(Me)cyclobutyl 2-Me-4-MeO-5-F—Ph 248 Me CH(Me)cyclopropyl2-Me-4-MeO-5-F—Ph 249 Me CH(OMe)cyclopropyl 2-Me-4-MeO-5-F—Ph 250 MeCH(Et)cyclobutyl 2-Me-4-MeO-5-F—Ph 251 Me CH(Et)cyclopropyl2-Me-4-MeO-5-F—Ph 252 Me CH(Me)CH₂-cyclobutyl 2-Me-4-MeO-5-F—Ph 253 MeCH(OMe)CH₂-cyclobutyl 2-Me-4-MeO-5-F—Ph 254 Me CH(OH)CH₂-cyclobutyl2-Me-4-MeO-5-F—Ph 255 Me CH(Me)CH₂-cyclopropyl 2-Me-4-MeO-5-F—Ph 256 MeCH(Et)CH₂-cyclobutyl 2-Me-4-MeO-5-F—Ph 257 Me CH(Et)CH₂-cyclopropyl2-Me-4-MeO-5-F—Ph 258 Me CH(OMe)CH₂-cyclobutyl 2-Me-4-MeO-5-F—Ph 259 MeCH(OMe)CH₂-cyclopropyl 2-Me-4-MeO-5-F—Ph 260 Me CH(OEt)CH₂-cyclobutyl2-Me-4-MeO-5-F—Ph 261 Me CH(OEt)CH₂-cyclopropyl 2-Me-4-MeO-5-F—Ph 262 MeCH(CH₂OMe)cyclobutyl 2-Me-4-MeO-5-F—Ph 263 Me CH(CH₂OMe)cyclopropyl2-Me-4-MeO-5-F—Ph 264 Me CH(CH₂OEt)cyclobutyl 2-Me-4-MeO-5-F—Ph 265 MeCH(CH₂OEt)cyclopropyl 2-Me-4-MeO-5-F—Ph 266 Me CH(cyclobutyl)₂2-Me-4-MeO-5-F—Ph 267 Me CH(cyclopropyl)₂ 2-Me-4-MeO-5-F—Ph 268 MeCH(Et)CH₂CONMe₂ 2-Me-4-MeO-5-F—Ph 269 Me CH(Et)CH₂CH₂NMe₂2-Me-4-MeO-5-F—Ph 270 Me CH(CH₂OMe)Me 2-Me-4-MeO-5-F—Ph 271 MeCH(CH₂OMe)Et 2-Me-4-MeO-5-F—Ph 272 Me CH(CH₂OMe)Pr 2-Me-4-MeO-5-F—Ph 273Me CH(CH₂OEt)Me 2-Me-4-MeO-5-F—Ph 274 Me CH(CH₂OEt)Et 2-Me-4-MeO-5-F—Ph275 Me CH(CH₂OEt)Pr 2-Me-4-MeO-5-F—Ph 276 Me CH(CH₂C≡CMe)Et2-Me-4-MeO-5-F—Ph 277 Me CH(CH₂C≡CMe)Et 2-Me-4-MeO-5-F—Ph 278 MeCH(Et)CH₂OH 2,5-(Me)₂-4-MeO—Ph 279 Me CH(Et)CH₂OMe 2,5-(Me)₂-4-MeO—Ph280 Me CH(Et)CH₂CH₂OMe 2,5-(Me)₂-4-MeO—Ph 281 Me 3-pentyl2,5-(Me)₂-4-MeO—Ph 282 Me 2-butyl 2,5-(Me)₂-4-MeO—Ph 283 Me cyclobutyl2,5-(Me)₂-4-MeO—Ph 284 Me cyclopentyl 2,5-(Me)₂-4-MeO—Ph 285 MeCH(Me)cyclobutyl 2,5-(Me)₂-4-MeO—Ph 286 Me CH(Me)cyclopropyl2,5-(Me)₂-4-MeO—Ph 287 Me CH(Et)cyclobutyl 2,S-(Me)₂-4-MeO—Ph 288 MeCH(Et)cyclopropyl 2,5-(Me)₂-4-MeO—Ph 289 Me CH(Me)CH₂-cyclobutyl2,5-(Me)₂-4-MeO—Ph 290 Me CH(Me)CH₂-cyclopropyl 2,5-(Me)₂-4-MeO—Ph 291Me CH(Et)CH₂-cyclobutyl 2,5-(Me)₂-4-MeO—Ph 292 Me CH(Et)CH₂-cyclopropyl2,5-(Me)₂-4-MeO—Ph 293 Me CH(CH₂OMe)cyclobutyl 2,5-(Me)₂-4-MeO—Ph 294 MeCH(CH₂OMe)cyclopropyl 2,5-(Me)₂-4-MeO—Ph 295 Me CH(CH₂OEt)cyclobutyl2,5-(Me)₂-4-MeO—Ph 296 Me CH(CH₂OEt)cyclopropyl 2,5-(Me)₂-4-MeO—Ph 297Me CH(cyclobutyl)₂ 2,5-(Me)₂-4-MeO—Ph 298 Me CH(cyclopropyl)₂2,5-(Me)₂-4-MeO—Ph 299 Me CH(Et)CH₂CONMe₂ 2,5-(Me)₂-4-MeO—Ph 300 MeCH(Et)CH₂CH₂NMe₂ 2,5-(Me)₂-4-MeO—Ph 301 Me CH(CH₂OMe)Me2,5-(Me)₂-4-MeO—Ph 302 Me CH(CH₂OMe)Et 2,5-(Me)₂-4-MeO—Ph 303 MeCH(CH₂OMe)Pr 2,5-(Me)₂-4-MeO—Ph 304 Me CH(CH₂OEt)Me 2,5-(Me)₂-4-MeO—Ph305 Me CH(CH₂OEt)Et 2,5-(Me)₂-4-MeO—Ph 306 Me CH(CH₂OEt)Pr2,5-(Me)₂-4-MeO—Ph 307 Me CH(CH₂C≡CMe)Et 2,5-(Me)₂-4-MeO—Ph 308 MeCH(CH₂CH═CHMe)Et 2,5-(Me)₂-4-MeO—Ph 309 Me CH(Et)CH₂OH2-Me-6-Me₂N-pyrid-3-yl 310 Me CH(Et)CH₂OMe 2-Me-6-Me₂N-pyrid-3-yl 311 MeCH(Et)CH₂CH₂OMe 2-Me-6-Me₂N-pyrid-3-yl 312 Me 3-pentyl2-Me-6-Me₂N-pyrid-3-yl 313 Me 2-pentyl 2-Me-6-Me₂N-pyrid-3-yl 314 Me2-butyl 2-Me-6-Me₂N-pyrid-3-yl 315 Me cyclobutyl 2-Me-6-Me₂N-pyrid-3-yl316 Me cyclopentyl 2-Me-6-Me₂N-pyrid-3-yl 317 Me CH(Me)cyclobutyl2-Me-6-Me₂N-pyrid-3-yl 318 Me CH(Me)cyclopropyl 2-Me-6-Me₂N-pyrid-3-yl319 Me CH(Et)cyclobutyl 2-Me-6-Me₂N-pyrid-3-yl 320 Me CH(Et)cyclopropyl2-Me-6-Me₂N-pyrid-3-yl 321 Me CH(Me)CH₂-cyclobutyl2-Me-6-Me₂N-pyrid-3-yl 322 Me CH(Me)CH₂-cyclopropyl2-Me-6-Me₂N-pyrid-3-yl 323 Me CH(Et)CH₂-cyclobutyl2-Me-6-Me₂N-pyrid-3-yl 324 Me CH(Et)CH₂-cyclopropyl2-Me-6-Me₂N-pyrid-3-yl 325 Me CH(CH₂OMe)cyclobutyl2-Me-6-Me₂N-pyrid-3-yl 326 Me CH(CH₂OMe)cyclopropyl2-Me-6-Me₂N-pyrid-3-yl 327 Me CH(CH₂OEt)cyclobutyl2-Me-6-Me₂N-pyrid-3-yl 328 Me CH(CH₂OEt)cyclopropyl2-Me-6-Me₂N-pyrid-3-yl 329 Me CH(cyclobutyl)₂ 2-Me-6-Me₂N-pyrid-3-yl 330Me CH(cyclopropyl)₂ 2-Me-6-Me₂N-pyrid-3-yl 331 Me CH(Et)CH₂CONMe₂2-Me-6-Me₂N-pyrid-3-yl 332 Me CH(Et)CH₂CH₂NMe₂ 2-Me-6-Me₂N-pyrid-3-yl333 Me CH(CH₂OMe)Me 2-Me-6-Me₂N-pyrid-3-yl 334 Me CH(CH₂OMe)Et2-Me-6-Me₂N-pyrid-3-yl 335 Me CH(CH₂OMe)Pr 2-Me-6-Me₂N-pyrid-3-yl 336 MeCH(CH₂OEt)Me 2-Me-6-Me₂N-pyrid-3-yl 337 Me CH(CH₂OEt)Et2-Me-6-Me₂N-pyrid-3-yl 338 Me CH(CH₂OEt)Pr 2-Me-6-Me₂N-pyrid-3-yl 339 MeCH(CH₂C≡CMe)Et 2-Me-6-Me₂N-pyrid-3-yl 340 Me CH(CH₂CH═CHMe)Et2-Me-6-Me₂N-pyrid-3-yl 341 Me CH(Et)CH₂OH 4-Me-2-Me₂N-pyrid-5-yl 342 MeCH(Et)CH₂OMe 4-Me-2-Me₂N-pyrid-5-yl 343 Me CH(Et)CH₂CH₂OMe4-Me-2-Me₂N-pyrid-5-yl 344 Me 3-pentyl 4-Me-2-Me₂N-pyrid-5-yl 345 Me2-pentyl 4-Me-2-Me₂N-pyrid-5-yl 346 Me 2-butyl 4-Me-2-Me₂N-pyrid-5-yl347 Me cyclobutyl 4-Me-2-Me₂N-pyrid-5-yl 348 Me cyclopentyl4-Me-2-Me₂N-pyrid-5-yl 349 Me CH(Me)cyclobutyl 4-Me-2-Me₂N-pyrid-5-yl350 Me CH(Me)cyclopropyl 4-Me-2-Me₂N-pyrid-5-yl 351 Me CH(Et)cyclobutyl4-Me-2-Me₂N-pyrid-5-yl 352 Me CH(Et)cyclopropyl 4-Me-2-Me₂N-pyrid-5-yl353 Me CH(Me)CH₂-cyclobutyl 4-Me-2-Me₂N-pyrid-5-yl 354 MeCH(Me)CH₂-cyclopropyl 4-Me-2-Me₂N-pyrid-5-yl 355 Me CH(Et)CH₂-cyclobutyl4-Me-2-Me₂N-pyrid-5-yl 356 Me CH(Et)CH₂-cyclopropyl4-Me-2-Me₂N-pyrid-5-yl 357 Me CH(CH₂OMe)cyclobutyl4-Me-2-Me₂N-pyrid-5-yl 358 Me CH(CH₂OMe)cyclopropyl4-Me-2-Me₂N-pyrid-5-yl 359 Me CH(CH₂OEt)cyclobutyl4-Me-2-Me₂N-pyrid-5-yl 360 Me CH(CH₂OEt)cyclopropyl4-Me-2-Me₂N-pyrid-5-yl 361 Me CH(cyclobutyl)₂ 4-Me-2-Me₂N-pyrid-5-yl 362Me CH(cyclopropyl)₂ 4-Me-2-Me₂N-pyrid-5-yl 363 Me CH(Et)CH₂CONMe₂4-Me-2-Me₂N-pyrid-5-yl 364 Me CH(Et)CH₂CH₂NMe₂ 4-Me-2-Me₂N-pyrid-5-yl365 Me CH(CH₂OMe)Me 4-Me-2-Me₂N-pyrid-5-yl 366 Me CH(CH₂OMe)Et4-Me-2-Me₂N-pyrid-5-yl 367 Me CH(CH₂OMe)Pr 4-Me-2-Me₂N-pyrid-5-yl 368 MeCH(CH₂OEt)Me 4-Me-2-Me₂N-pyrid-5-yl 369 Me CH(CH₂OEt)Et4-Me-2-Me₂N-pyrid-5-yl 370 Me CH(CH₂OEt)Pr 4-Me-2-Me₂N-pyrid-5-yl 371 MeCH(CH₂C≡CMe)Et 4-Me-2-Me₂N-pyrid-5-yl 372 Me CH(CH₂CH═CHMe)Et4-Me-2-Me₂N-pyrid-5-yl 373 Me CH(Et)CH₂OH 2-Me-6-MeO-pyrid-3-yl 374 MeCH(Et)CH₂OMe 2-Me-6-MeO-pyrid-3-yl 375 Me CH(Et)CH₂CH₂OMe2-Me-6-MeO-pyrid-3-yl 376 Me 3-pentyl 2-Me-6-MeO-pyrid-3-yl 377 Me2-pentyl 2-Me-6-MeO-pyrid-3-yl 378 Me 2-butyl 2-Me-6-MeO-pyrid-3-yl 379Me cyclobutyl 2-Me-6-MeO-pyrid-3-yl 380 Me cyclopentyl2-Me-6-MeO-pyrid-3-yl 381 Me CH(Me)cyclobutyl 2-Me-6-MeO-pyrid-3-yl 382Me CH(Me)cyclopropyl 2-Me-6-MeO-pyrid-3-yl 383 Me CH(Et)cyclobutyl2-Me-6-MeO-pyrid-3-yl 384 Me CH(Et)cyclopropyl 2-Me-6-MeO-pyrid-3-yl 385Me CH(Me)CH₂-cyclobutyl 2-Me-6-MeO-pyrid-3-yl 386 MeCH(Me)CH₂-cyclopropyl 2-Me-6-MeO-pyrid-3-yl 387 Me CH(Et)CH₂-cyclobutyl2-Me-6-MeO-pyrid-3-yl 388 Me CH(Et)CH₂-cyclopropyl 2-Me-6-MeO-pyrid-3-yl389 Me CH(CH₂OMe)cyclobutyl 2-Me-6-MeO-pyrid-3-yl 390 MeCH(CH₂OMe)cyclopropyl 2-Me-6-MeO-pyrid-3-yl 391 Me CH(CH₂OEt)cyclobutyl2-Me-6-MeO-pyrid-3-yl 392 Me CH(CH₂OEt)cyclopropyl 2-Me-6-MeO-pyrid-3-yl393 Me CH(cyclobutyl)₂ 2-Me-6-MeO-pyrid-3-yl 394 Me CH(cyclopropyl)₂2-Me-6-MeO-pyrid-3-yl 395 Me CH(Et)CH₂CONMe₂ 2-Me-6-MeO-pyrid-3-yl 396Me CH(Et)CH₂CH₂NMe₂ 2-Me-6-MeO-pyrid-3-yl 397 Me CH(CH₂OMe)Me2-Me-6-MeO-pyrid-3-yl 398 Me CH(CH₂OMe)Et 2-Me-6-MeO-pyrid-3-yl 399 MeCH(CH₂OMe)Pr 2-Me-6-MeO-pyrid-3-yl 400 Me CH(CH₂OEt)Me2-Me-6-MeO-pyrid-3-yl 401 Me CH(CH₂OEt)Et 2-Me-6-MeO-pyrid-3-yl 402 MeCH(CH₂OEt)Pr 2-Me-6-MeO-pyrid-3-yl 403 Me CH(CH₂C≡CMe)Et2-Me-6-MeO-pyrid-3-yl 404 Me CH(CH₂CH═CHMe)Et 2-Me-6-MeO-pyrid-3-yl 405Me CH(Et)CH₂OH 4-Me-2-MeO-pyrid-5-yl 406 Me CH(Et)CH₂OMe4-Me-2-MeO-pyrid-5-yl 407 Me CH(Et)CH₂CH₂OMe 4-Me-2-MeO-pyrid-5-yl 408Me 3-pentyl 4-Me-2-MeO-pyrid-5-yl 409 Me 2-pentyl 4-Me-2-MeO-pyrid-5-yl410 Me 2-butyl 4-Me-2-MeO-pyrid-5-yl 411 Me cyclobutyl4-Me-2-MeO-pyrid-5-yl 412 Me cyclopentyl 4-Me-2-MeO-pyrid-5-yl 413 MeCH(Me)cyclobutyl 4-Me-2-MeO-pyrid-5-yl 414 Me CH(Me)cyclopropyl4-Me-2-MeO-pyrid-5-yl 415 Me CH(Et)cyclobutyl 4-Me-2-MeO-pyrid-5-yl 416Me CH(Et)cyclopropyl 4-Me-2-MeO-pyrid-5-yl 417 Me CH(Me)CH₂-cyclobutyl4-Me-2-MeO-pyrid-5-yl 418 Me CH(Me)CH₂-cyclopropyl 4-Me-2-MeO-pyrid-5-yl419 Me CH(Et)CH₂-cyclobutyl 4-Me-2-MeO-pyrid-5-yl 420 MeCH(Et)CH₂-cyclopropyl 4-Me-2-MeO-pyrid-5-yl 421 Me CH(CH₂OMe)cyclobutyl4-Me-2-MeO-pyrid-5-yl 422 Me CH(CH₂OMe)cyclopropyl 4-Me-2-MeO-pyrid-5-yl423 Me CH(CH₂OEt)cyclobutyl 4-Me-2-MeO-pyrid-5-yl 424 MeCH(CH₂OEt)cyclopropyl 4-Me-2-MeO-pyrid-5-yl 425 Me CH(cyclobutyl)₂4-Me-2-MeO-pyrid-5-yl 426 Me CH(cyclopropyl)₂ 4-Me-2-MeO-pyrid-5-yl 427Me CH(Et)CH₂CONMe₂ 4-Me-2-MeO-pyrid-5-yl 428 Me CH(Et)CH₂CH₂NMe₂4-Me-2-MeO-pyrid-5-yl 429 Me CH(CH₂OMe)Me 4-Me-2-MeO-pyrid-5-yl 430 MeCH(CH₂OMe)Et 4-Me-2-MeO-pyrid-5-yl 431 Me CH(CH₂OMe)Pr4-Me-2-MeO-pyrid-5-yl 432 Me CH(CH₂OEt)Me 4-Me-2-MeO-pyrid-5-yl 433 MeCH(CH₂OEt)Et 4-Me-2-MeO-pyrid-5-yl 434 Me CH(CH₂OEt)Pr4-Me-2-MeO-pyrid-5-yl 435 Me CH(CH₂C≡CMe)Et 4-Me-2-MeO-pyrid-5-yl 436 MeCH(CH₂CH═CHMe)Et 4-Me-2-MeO-pyrid-5-yl 536 H 2-pentyl 2,4-Cl₂-5-F—Ph159-160 537 Me 2-pentyl 2,4-Cl₂-5-F—Ph 120-121 538 Me (R)-2-butyl2,4-Cl₂—Ph 105-107 539 Me (S)-2-butyl 2,4-Cl₂—Ph oil 540 Me 2-pentyl4-Br-2-Cl—Ph 97-98 541 Me 2-pentyl Ph oil 542 Me 2-pentyl 4-OMe-Ph oil543 Me CH₂OCH₂Ph 2,4-Cl₂—Ph oil 544 Me H 2,4-Cl₂—Ph 234-235 545 HCH₂OCH₂Ph 2,4-Cl₂—Ph 174-175 546 Me n-butyl 2,4-Cl₂—Ph oil 547 MeCH₂CH₂OMe 2,4-Cl₂—Ph oil 548 Me 3-heptyl 2,4-Cl₂—Ph 110-111 549 Me(S)-2-pentyl 2,4-Cl₂—Ph oil 550 Me (R)-2-pentyl 2,4-Cl₂—Ph oil 551 MeCH(Et)CH₂C≡CH 2,4-Cl₂—Ph oil 552 Me 2-hexyl 2,4-Cl₂—Ph oil 553 Me3-hexyl 2,4-Cl₂—Ph 135-136 554 Me CH(Et)CH₂CH₂CH═CH₂ 2,4-Cl₂—Ph 106-107555 Me CH(CH₂CH═CH₂)₂ 2,4-Cl₂—Ph oil 556 Me CH(Me)CH₂OCH₃ 2,4-Cl₂—Ph oil557 Me CH(n-C₃H₇)-cyclopropyl 2,4-Cl₂—Ph 139-140 558 MeCH(Ph)-cyclopropyl 2,4-Cl₂—Ph 172-173 559 Me CH(4-OMe-Ph)-cyclopropyl2,4-Cl₂—Ph oil 560 Me CH(4-Me-Ph)-cyclopropyl 2,4-Cl₂—Ph oil 561 MeCH(4-F—Ph)-cyclopropyl 2,4-Cl₂—Ph oil 562 Me CH₂CH(CH₃)₂ 2,4-Cl₂—Ph oil563 Me CH₂C(═CH₂)Me 2,4-Cl₂—Ph 126-127 564 Me CH₂CH₂CH(CH₃)₂ 2,4-Cl₂—Ph105-106 565 Me CH₂CH₂CH═CH₂ 2,4-Cl₂—Ph oil 566 Me CH₂C≡CMe 2,4-Cl₂—Ph148-149 567 Me (R)-CH₂CH(Me)CH₂CH₃ 2,4-Cl₂—Ph oil 568 Me(S)-CH₂CH(Me)CH₂CH₃ 2,4-Cl₂—Ph oil 569 Me CH₂COCH₂CH₃ 2,4-Cl₂—Ph 104-105570 Me CH₂CH(CH₂CH₃)₂ 2,4-Cl₂—Ph oil 571 Me n-pentyl 2,4-Cl₂—Ph oil 572Me CH₂(CH₂)₂CH═CH₂ 2,4-Cl₂—Ph oil 573 Me CH₂CH═CHCH₂CH₃ 2,4-Cl₂—Ph oil574 Me CH₂(2-Cl—Ph) 2,4-Cl₂—Ph 163-165 575 Me CH₂(3-Cl—Ph) 2,4-Cl₂—Ph82-84 576 Me CH₂(4-Cl—Ph) 2,4-Cl₂—Ph 149-150 577 Me CH₂(2,4-Cl₂—Ph)2,4-Cl₂—Ph 85-87 578 Me CH₂(2,4-F₂—Ph) 2,4-Cl₂—Ph oil 579 Me CH(Me)Ph2,4-Cl₂—Ph 179-180 580 Me CH₂CH₂Ph 2,4-Cl₂—Ph oil 581 Me CH₂-cyclobutyl2,4-Cl₂—Ph oil 582 Me 2-pentyl 2-4-CF₃—Ph oil 583 Me 2-pentyl2-Cl-4-F—Ph oil 584 Me 2-pentyl 2,4-Cl₂—Ph oil 585 Me 2-pentyl2,6-(OMe)₂-pyrid-5-yl oil

TABLE 2

Ex. R₃ R₂ Ar mp (° C.) 437 Me CH(Et)CH₂OH 2,4-Cl₂—Ph 438 Me CH(Et)CH₂OMe2,4-Cl₂—Ph 439 Me CH(Et)CH₂CH₂OMe 2,4-Cl₂—Ph 440 Me 3-pentyl 2,4-Cl₂—Ph441 Me 2-pentyl 2,4-Cl₂—Ph 442 Me 2-butyl 2,4-Cl₂—Ph 443 Me cyclobutyl2,4-Cl₂—Ph 444 Me cyclopentyl 2,4-Cl₂—Ph 445 Me CH(Me)cyclobutyl2,4-Cl₂—Ph 446 Me CH(Me)cyclopropyl 2,4-Cl₂—Ph 447 Me CH(Et)cyclobutyl2,4-Cl₂—Ph 448 Me CH(Et)cyclopropyl 2,4-Cl₂—Ph 449 MeCH(Me)CH₂-cyclobutyl 2,4-Cl₂—Ph 450 Me CH(OH)CH₂-cyclobutyl 2,4-Cl₂—Ph451 Me CH(Me)CH₂-cyclopropyl 2,4-Cl₂—Ph 452 Me CH(Et)CH₂-cyclobutyl2,4-Cl₂—Ph 453 Me CH(Et)CH₂-cyclopropyl 2,4-Cl₂—Ph 454 MeCH(CH₂OMe)cyclobutyl 2,4-Cl₂—Ph 455 Me CH(CH₂OMe)cyclopropyl 2,4-Cl₂—Ph456 Me CH(CH₂OEt)cyclobutyl 2,4-Cl₂—Ph 457 Me CH(CH₂OEt)cyclopropyl2,4-Cl₂—Ph 458 Me CH(cyclobutyl)₂ 2,4-Cl₂—Ph 459 Me CH(cyclopropyl)₂2,4-Cl₂—Ph 460 Me CH(Et)CH₂CONMe₂ 2,4-Cl₂—Ph 461 Me CH(Et)CH₂CH₂NMe₂2,4-Cl₂—Ph 462 Me CH(CH₂OMe)Me 2,4-Cl₂—Ph 463 Me CH(CH₂OMe)Et 2,4-Cl₂—Ph464 Me CH(CH₂OMe)Pr 2,4-Cl₂—Ph 465 Me CH(CH₂OEt)Me 2,4-Cl₂—Ph 466 MeCH(CH₂OEt)Et 2,4-Cl₂—Ph 467 Me CH(CH₂OEt)Pr 2,4-Cl₂—Ph 468 MeCH(CH₂C≡CMe)Et 2,4-Cl₂—Ph 469 Me CH(CH₂CH═CHMe)Et 2,4-Cl₂—Ph

TABLE 3

Ex. R₃ R₂ Ar mp (° C.) 470 Me CH(Et)CH₂OH 2,4-Cl₂—Ph 471 Me CH(Et)CH₂OMe2,4-Cl₂—Ph 472 Me CH(Et)CH₂CH₂OMe 2,4-Cl₂—Ph 473 Me 3-pentyl 2,4-Cl₂—Ph474 Me 2-pentyl 2,4-Cl₂—Ph 475 Me 2-butyl 2,4-Cl₂—Ph 476 Me cyclobutyl2,4-Cl₂—Ph 477 Me cyclopentyl 2,4-Cl₂—Ph 478 Me CH(Me)cyclobutyl2,4-Cl₂—Ph 479 Me CH(Me)cyclopropyl 2,4-Cl₂—Ph 480 Me CH(Et)cyclobutyl2,4-Cl₂—Ph 481 Me CH(Et)cyclopropyl 2,4-Cl₂—Ph 482 MeCH(Me)CH₂-cyclobutyl 2,4-Cl₂—Ph 483 Me CH(OH)CH₂-cyclobutyl 2,4-Cl₂—Ph484 Me CH(Me)CH₂-cyclopropyl 2,4-Cl₂—Ph 485 Me CH(Et)CH₂-cyclobutyl2,4-Cl₂—Ph 486 Me CH(Et)CH₂-cyclopropyl 2,4-Cl₂—Ph 487 MeCH(CH₂OMe)cyclobutyl 2,4-Cl₂—Ph 488 Me CH(CH₂OMe)cyclopropyl 2,4-Cl₂—Ph489 Me CH(CH₂OEt)cyclobutyl 2,4-Cl₂—Ph 490 Me CH(CH₂OEt)cyclopropyl2,4-Cl₂—Ph 491 Me CH(cyclobutyl)₂ 2,4-Cl₂—Ph 492 Me CH(cyclopropyl)₂2,4-Cl₂—Ph 493 Me CH(Et)CH₂CONMe₂ 2,4-Cl₂—Ph 494 Me CH(Et)CH₂CH₂NMe₂2,4-Cl₂—Ph 495 Me CH(CH₂OMe)Me 2,4-Cl₂—Ph 496 Me CH(CH₂OMe)Et 2,4-Cl₂—Ph497 Me CH(CH₂OMe)Pr 2,4-Cl₂—Ph 498 Me CH(CH₂OEt)Me 2,4-Cl₂—Ph 499 MeCH(CH₂OEt)Et 2,4-Cl₂—Ph 500 Me CH(CH₂OEt)Pr 2,4-Cl₂—Ph 501 MeCH(CH₂C≡CMe)Et 2,4-Cl₂—Ph 502 Me CH(CH₂C≡CMe)Et 2,4-Cl₂—Ph

TABLE 4

Ex. R₃ R₂ Ar mp (° C.) 503 Me CH(Et)CH₂OH 2,4-Cl₂—Ph 504 Me CH(Et)CH₂OMe2,4-Cl₂—Ph 505 Me CH(Et)CH₂CH₂OMe 2,4-Cl₂—Ph 506 Me 3-pentyl 2,4-Cl₂—Ph507 Me 2-pentyl 2,4-Cl₂—Ph 508 Me 2-butyl 2,4-Cl₂—Ph 509 Me cyclobutyl2,4-Cl₂—Ph 510 Me cyclopentyl 2,4-Cl₂—Ph 511 Me CH(Me)cyclobutyl2,4-Cl₂—Ph 512 Me CH(Me)cyclopropyl 2,4-Cl₂—Ph 513 Me CH(Et)cyclobutyl2,4-Cl₂—Ph 514 Me CH(Et)cyclopropyl 2,4-Cl₂—Ph 515 MeCH(Me)CH₂-cyclobutyl 2,4-Cl₂—Ph 516 Me CH(OH)CH₂-cyclobutyl 2,4-Cl₂—Ph517 Me CH(Me)CH₂-cyclopropyl 2,4-Cl₂—Ph 518 Me CH(Et)CH₂-cyclobutyl2,4-Cl₂—Ph 519 Me CH(Et)CH₂-cyclopropyl 2,4-Cl₂—Ph 520 MeCH(CH₂OMe)cyclobutyl 2,4-Cl₂—Ph 521 Me CH(CH₂OMe)cyclopropyl 2,4-Cl₂—Ph522 Me CH(CH₂OEt)cyclobutyl 2,4-Cl₂—Ph 523 Me CH(CH₂OEt)cyclopropyl2,4-Cl₂—Ph 524 Me CH(cyclobutyl)₂ 2,4-Cl₂—Ph 525 Me CH(cyclopropyl)₂2,4-Cl₂—Ph 526 Me CH(Et)CH₂CONMe₂ 2,4-Cl₂—Ph 527 Me CH(Et)CH₂CH₂NMe₂2,4-Cl₂—Ph 528 Me CH(CH₂OMe)Me 2,4-Cl₂—Ph 529 Me CH(CH₂OMe)Et 2,4-Cl₂—Ph530 Me CH(CH₂OMe)Pr 2,4-Cl₂—Ph 531 Me CH(CH₂OEt)Me 2,4-Cl₂—Ph 532 MeCH(CH₂OEt)Et 2,4-Cl₂—Ph 533 Me CH(CH₂OEt)Pr 2,4-Cl₂—Ph 534 MeCH(CH₂C≡CMe)Et 2,4-Cl₂—Ph 535 Me CH(CH₂CH═CHMe)Et 2,4-Cl₂—Ph

Examples shown above in Tables 1-4 wherein R³ is H, C₂H₅, C₃H₇ orC₁₋₆alkylC₃₋₆ cycloalkyl are also readily prepared according to theprocedures disclosed herein.

CRF Receptor Binding Assay for the Evaluation of Biological Activity

Radioligand Binding Experiments

Compounds of the invention were tested for in vitro activity as CRFreceptor antagonists. The tests described below demonstrated that theexamples tested had K_(i)s of 10,000 nM or less and are thus useful asCRF receptor antagonists. Preferred antagonists have or will have aK_(i) of 1,000 nM or less. Radioligand binding experiments wereperformed with membranes from rat frontal cortex to determine bindingaffinities (K_(i)'s) of test compounds for the rat CRH₁ receptor using amodified version of methods described earlier (see E. B. DeSouza, J.Neurosci, 7:88, 1987). Rat cortex was homogenized in tissue buffer(containing 50 mM HEPES, 10 mM MgCl₂, 2 mM EGTA, and 1 μg/ml each ofaprotonin, leupeptin, and pepstatin, pH 7.0 @ 23° C.) using a BrinkmanPolytron (PT-10, setting 6 for 10 sec). The homogenate was centrifugedat 48,000×g for 12 min and the resulting pellet was washed by twosequential re-suspension and centrifugation steps. The final pellet wassuspended to tissue buffer to a working concentration of 0.1 mg/mlprotein. Protein determinations were made using the bicinchoninic acid(BCA) assay (Pierce, Rockford, Ill.) with bovine serum albumin as thestandard.

All test compounds were prepared in assay buffer, which was identical tothe tissue buffer except for the inclusion of 0.15 mM bacitracin and0.1% w/v ovalbumin. Binding assay were conducted in disposablepolypropylene 96-well plates (Costar Corp., Cambridge, Mass.) andinitiated by the addition of 100 μl membrane homogenate (containing40-60 μg protein) to 200 μl of assay buffer containing radioligands (150pM, final concentration, [¹²⁵I] tyr° ovine CRH; New England Nuclear, MA)and competing test compounds. Specific binding was determined in thepresence of 10 μM α-helical CRH. Competition experiments were conductedusing 12 concentrations of ligand (ranging from 1×10⁻¹¹ to 1×10⁻⁵ M).The reactions mixtures were incubated to equilibrium for 2 hr at 23° C.and terminated by rapid filtration using a cell harvester (InotechBiosystems Inc., Lansing Mich.) over GFF glass-fibers (pre-soaked in0.3% v/v polyethyleneimine). Filters were rapidly washed 3× with 0.3 mlcold wash buffer (PBS, pH 7.0, containing 0.01% Triton X-100), dried,and counted in a gamma counter at 80% efficiency.

Binding affinities (K_(i)'s) of ligands for the CRH₁ receptor werecalculated using the iterative nonlinear regression curve-fittingprograms (LIGAND) of Munson and Rodbard (Anal. Biochem. 1980, 107,220-239) or Prism (GraphPad Prism, San Diego, Calif.). Data werebest-fit by the one-site/state competition equation.

Inhibition of CRF-Stimulated Adenylate Cyclase Activity

Inhibition of CRF-stimulated adenylate cyclase activity can be performedas described by G. Battaglia et al. Synapse 1:572 (1987). Briefly,assays are carried out at 37° C. for 10 min in 200 ml of buffercontaining 100 mM Tris-HCl (pH 7.4 at 37° C.), 10 mM MgCl₂, 0.4 mM EGTA,0.1% BSA, 1 mM isobutylmethylxanthine (IBMX), 250 units/mlphosphocreatine kinase, 5 mM creatine phosphate, 100 mM guanosine5′-triphosphate, 100 nM OCRF, antagonist peptides (concentration range10⁻⁹ to 10^(−6m)) and 0.8 mg original wet weight tissue (approximately40-60 mg protein). Reactions are initiated by the addition of 1 mMATP/³²P]ATP (approximately 2-4 mCi/tube) and terminated by the additionof 100 ml of 50 mM Tris-HCL, 45 mM ATP and 2% sodium dodecyl sulfate. Inorder to monitor the recovery of cAMP, 1 μl of [³H]cAMP (approximately40,000 dpm) is added to each tube prior to separation. The separation of[³²P]cAMP from [³²P]ATP is performed by sequential elution over Dowexand alumina columns.

In vivo Biological Assay

The in vivo activity of the compounds of the present invention can beassessed using any one of the biological assays available and acceptedwithin the art. Illustrative of these tests include the Acoustic StartleAssay, the Stair Climbing Test, and the Chronic Administration Assay.These and other models useful for the testing of compounds of thepresent invention have been outlined in C. W. Berridge and A. J. DunnBrain Research Reviews 15:71 (1990). Compounds may be tested in anyspecies of rodent or small mammal.

Compounds of this invention have utility in the treatment of inbalancesassociated with abnormal levels of corticotropin releasing factor inpatients suffering from depression, affective disorders, and/or anxiety.

Compounds of this invention can be administered to treat theseabnormalities by means that produce contact of the active agent with theagent's site of action in the body of a mammal. The compounds can beadministered by any conventional means available for use in conjunctionwith pharmaceuticals either as individual therapeutic agent or incombination of therapeutic agents. They can be administered alone, butwill generally be administered with a pharmaceutical carrier selected onthe basis of the chosen route of administration and standardpharmaceutical practice.

The dosage administered will vary depending on the use and known factorssuch as pharmacodynamic character of the particular agent, and its modeand route of administration; the recipient's age, weight, and health;nature and extent of symptoms; kind of concurrent treatment; frequencyof treatment; and desired effect. For use in the treatment of saiddiseases or conditions, the compounds of this invention can be orallyadministered daily at a dosage of the active ingredient of 0.002 to 200mg/kg of body weight. Ordinarily, a dose of 0.01 to 10 mg/kg in divideddoses one to four times a day, or in sustained release formulation willbe effective in obtaining the desired pharmacological effect.

Dosage forms (compositions) suitable for administration contain fromabout 1 mg to about 100 mg of active ingredient per unit. In thesepharmaceutical compositions, the active ingredient will ordinarily bepresent in an amount of about 0.5 to 95% by weight based on the totalweight of the composition.

The active ingredient can be administered orally is solid dosage forms,such as capsules, tablets and powders; or in liquid forms such aselixirs, syrups, and/or suspensions. The compounds of this invention canalso be administered parenterally in sterile liquid dose formulations.

Gelatin capsules can be used to contain the active ingredient and asuitable carrier such as but not limited to lactose, starch, magnesiumstearate, steric acid, or cellulose derivatives. Similar diluents can beused to make compressed tablets. Both tablets and capsules can bemanufactured as sustained release products to provide for continuousrelease of medication over a period of time. Compressed tablets can besugar-coated or film-coated to mask any unpleasant taste, or used toprotect the active ingredients from the atmosphere, or to allowselective disintegration of the tablet in the gastrointestinal tract.

Liquid dose forms for oral administration can contain coloring orflavoring agents to increase patient acceptance.

In general, water, pharmaceutically acceptable oils, saline, aqueousdextrose (glucose), and related sugar solutions and glycols, such aspropylene glycol or polyethylene glycol, are suitable carriers forparenteral solutions. Solutions for parenteral administration preferablycontain a water soluble salt of the active ingredient, suitablestabilizing agents, and if necessary, butter substances. Antioxidizingagents, such as sodium bisulfite, sodium sulfite, or ascorbic acid,either alone or in combination, are suitable stabilizing agents. Alsoused are citric acid and its salts, and EDTA. In addition, parenteralsolutions can contain preservatives such as benzalkonium chloride,methyl- or propyl-paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in “Remington'sPharmaceutical Sciences”, A. Osol, a standard reference in the field.

Useful pharmaceutical dosage-forms for administration of the compoundsof this invention can be illustrated as follows:

Capsules

A large number of units capsules are prepared by filling standardtwo-piece hard gelatin capsules each with 100 mg of powdered activeingredient, 150 mg lactose, 50 mg cellulose, and 6 mg magnesiumstearate.

Soft Gelatin Capsules

A mixture of active ingredient in a digestible oil such as soybean,cottonseed oil, or olive oil is prepared and injected by means of apositive displacement was pumped into gelatin to form soft gelatincapsules containing 100 mg of the active ingredient. The capsules werewashed and dried.

Tablets

A large number of tablets are prepared by conventional procedures sothat the dosage unit was 100 mg active ingredient, 0.2 mg of colloidalsilicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystallinecellulose, 11 mg of starch, and 98.8 mg lactose. Appropriate coatingsmay be applied to increase palatability or delayed adsorption.

The compounds of this invention may also be used as reagents orstandards in the biochemical study of neurological function,dysfunction, and disease.

Although the present invention has been described and exemplified interms of certain preferred embodiments, other embodiments will beapparent to those skilled in the art. The invention is, therefore, notlimited to the particular embodiments described and exemplified, but iscapable of modification or variation without departing from the spiritof the invention, the full scope of which is delineated by the appendedclaims.

What is claimed is:
 1. A compound of Formula (1):

or geometric isomers thereof, stereoisomeric forms thereof, or mixturesof stereoisomeric forms thereof, or pharmaceutically acceptable salt orpro-drug forms thereof, wherein: X is O or S; A=N; Ar is selected fromphenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl,benzothienyl, benzofuranyl, 2,3-dihydrobenzofuranyl,2,3-dihydrobenzothienyl, indanyl, 1,2-benzopyranyl,3,4-dihydro-1,2-benzopyranyl, tetralinyl, each Ar optionally substitutedwith 1 to 5 R⁴ groups and each Ar is attached via an unsaturated carbonatom; R¹ is independently selected at each occurrence from H, C₁-C₄alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, halo, CN, C₁-C₄ haloalkyl, C₁-C₁₂hydroxyalkyl, C₂-C₁₂ alkoxyalkyl, C₂-C₁₀ cyanoalkyl, C₃-C₆ cycloalkyl,C₄-C₁₀ cycloalkylalkyl, NR⁹R¹⁰, C₁-C₄ alkyl-NR⁹R¹⁰, NR⁹COR¹⁰, OR¹¹, SHor S(O)_(n)R¹²; R² is selected from: —H, aryl, heteroaryl andheterocyclyl, or —C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₈cycloalkyl, C₅-C₈ cycloalkenyl, C₄-C₁₂ cycloalkylalkyl or C₆-C₁₀cycloalkenylalkyl, each optionally substituted with 1 to 3 substituentsindependently selected at each occurrence from C₁-C₆ alkyl, C₁₋₆alkyloxy-C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃-C₆ cycloalkyl, halo,C₁-C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³,NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl,heteroaryl and heterocyclyl; R³ is selected from: —H, aryl, heteroaryland heterocyclyl, or C₁-C₄ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₁₀ cycloalkylalkyl, each optionally substituted with 1to 3 substituents independently selected at each occurrence from C₁-C₆alkyl, C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl, cyano, OR¹⁵, SH,S(O)_(n)R¹²³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵, N(COR¹⁵)₂,NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroaryl andheterocyclyl; R⁴ is independently selected at each occurrence from:C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₆ cycloalkyl, C₄-C₁₂cycloalkylalkyl, NO₂, halo, CN, C₁-C₄ haloalkyl, NR⁶R⁷, NR⁶COR⁷,NR⁶CO₂R⁷, COR⁷, OR⁷, CONR⁶R⁷, CO(NOR⁹)R⁷, CO₂R⁷, or S(O)_(n)R⁷, whereeach such C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₆ cycloalkyland C₄-C₁₂ cycloalkylalkyl are optionally substituted with 1 to 3substituents independently selected at each occurrence from C₁-C₄ alkyl,NO₂, halo, CN, NR⁶R⁷, NR⁶COR⁷, NR⁶CO₂R⁷, COR⁷ OR⁷, CONR⁶R⁷, CO₂R⁷,CO(NOR⁹)R⁷, or S(O)_(n)R⁷; R⁶ and R⁷ are independently selected at eachoccurrence from: —H, —C₁-C₁₀ alkyl, C₃-C₁₀ alkenyl, C₃-C₁₀ alkynyl,C₁-C₁₀ haloalkyl with 1-10 halogens, C₂-C₈ alkoxyalkyl, C₃-C₆cycloalkyl, C₄-C₁₂ cycloalkylalkyl, C₅-C₁₀ cycloalkenyl, or C₆-C₁₄cycloalkenylalkyl, each optionally substituted with 1 to 3 substituentsindependently selected at each occurrence from C₁-C₆ alkyl, C₃-C₆cycloalkyl, halo, C₁-C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵,CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵,CONR¹⁶R¹⁵, aryl, heteroaryl or heterocyclyl, -aryl, aryl(C₁-C₄ alkyl),heteroaryl, heteroaryl(C₁-C₄ alkyl), heterocyclyl or heterocyclyl(C₁-C₄alkyl); alternatively, NR⁶R⁷ is piperidine, pyrrolidine, piperazine,N-methylpiperazine, morpholine or thiomorpholine, each optionallysubstituted with 1-3 C₁-C₄ alkyl groups; R⁸ is independently selected ateach occurrence from H or C₁-C₄ alkyl optionally substituted by halogen,C₁-C₄ alkoxy or C₁-C₄ halo-alkoxy (1 to 4 halogens); R⁹ and R¹⁰ areindependently selected at each occurrence from H, C₁-C₄ alkyl, or C₃-C₆cycloalkyl; R¹¹ is selected from H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, orC₃-C₆ cycloalkyl; R¹² is C₁-C₄ alkyl or C₁-C₄ haloalkyl; R¹³ is selectedfrom C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₂-C₈ alkoxyalkyl, C₃-C₆ cycloalkyl,C₄-C₁₂ cycloalkylalkyl, aryl, aryl(C₁-C₄ alkyl)-, heteroaryl orheteroaryl(C₁-C₄ alkyl)-; R¹⁵ and R¹⁶ are independently selected at eachoccurrence from H, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, C₄-C₁₆cycloalkylalkyl, except that for S(O)_(n)R¹⁵, R¹⁵ cannot be H; aryl isphenyl or naphthyl, each optionally substituted with 1 to 5 substituentsindependently selected at each occurrence from C₁-C₆ alkyl, C₃-C₆cycloalkyl, halo, C₁-C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹⁵, COR¹⁵,CO₂R¹⁵, OC(O)R¹⁵, NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹⁵, NR¹⁶R¹⁵,and CONR¹⁶R¹⁵; heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl,pyranyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl,indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl,isoxazolyl, pyrazolyl, 2,3-dihydrobenzothienyl or2,3-dihydrobenzofuranyl, each being optionally substituted with 1 to 5substituents independently selected at each occurrence from C₁-C₆ alkyl,C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹⁵,—COR¹⁵, CO₂R¹⁵, OC(O)R¹⁵, NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹⁵,NR¹⁶R¹⁵, and CONR¹⁶R¹⁵; heterocyclyl is saturated or partially saturatedheteroaryl, optionally substituted with 1 to 5 substituentsindependently selected at each occurrence from C₁-C₆ alkyl, C₃-C₆cycloalkyl, halo, C₁-C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹⁵, COR¹⁵,C₂R¹⁵, OC(O)R¹⁵, NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹⁵, NR¹⁵R¹⁶,and CONR¹⁶R¹⁵; and n is independently at each occurrence 0, 1 or
 2. 2.The compound according to claim 1 wherein Ar is phenyl or pyridyl, eachoptionally substituted with 1 to 4 R⁴ substituents.
 3. The compoundaccording to claim 1 wherein Ar is phenyl wherein phenyl is optionallysubstituted with 1 to 3 R⁴ substituents.
 4. The compound according toclaim 1 wherein R² is: —C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl,C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, C₄-C₁₂ cycloalkylalkyl or C₆-C₁₀cycloalkenylalkyl, each optionally substituted with 1 to 3 substituentsindependently selected at each occurrence from C₁-C₆ alkyl, C₃-C₆cycloalkyl, halo, C₁-C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵,CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵,CONR¹⁶R¹⁵, aryl, heteroaryl and heterocyclyl.
 5. The compound accordingto claim 1 wherein R¹, R² and R³ are independently selected from C₁₋₆alkyl or C₁₋₆ alkyloxy.
 6. A pharmaceutical composition comprising thecompound of claim 1 and a pharmaceutically acceptable carrier.
 7. Amethod of antagonizing a CRF receptor in a mammal comprising contactingthe receptor with a compound of the formula:

or geometric isomers thereof, stereoisomeric forms thereof, or mixturesof stereoisomeric forms thereof, or pharmaceutically acceptable salt orpro-drug forms thereof, wherein: X is O or S; A=N; Ar is selected fromphenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl,benzothienyl, benzofuranyl, 2,3-dihydrobenzofuranyl,2,3-dihydrobenzothienyl, indanyl, 1,2-benzopyranyl,3,4-dihydro-1,2-benzopyranyl, tetralinyl, each Ar optionally substitutedwith 1 to 5 R⁴ groups and each Ar is attached via an unsaturated carbonatom; R¹ is independently selected at each occurrence from H, C₁-C₄alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, halo, CN, C₁-C₄ haloalkyl, C₁-C₁₂hydroxyalkyl, C₂-C₁₂ alkoxyalkyl, C₂-C₁₀ cyanoalkyl, C₃-C₆ cycloalkyl,C₄-C₁₀ cycloalkylalkyl, NR⁹R¹⁰, C₁-C₄ alkyl-NR⁹R¹⁰, NR⁹COR¹⁰, OR¹¹, SHor S(O)_(n)R¹²; R² is selected from: —H, aryl, heteroaryl andheterocyclyl, or —C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₈cycloalkyl, C₅-C₈ cycloalkenyl, C₄-C₁₂ cycloalkylalkyl or C₆-C₁₀cycloalkenylalkyl, each optionally substituted with 1 to 3 substituentsindependently selected at each occurrence from C₁-C₆ alkyl, C₁₋₆alkyloxy C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃-C₆ cycloalkyl, halo,C₁-C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³,NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl,heteroaryl and heterocyclyl; R³ is selected from H, C₁-C₄ alkyl, C₃-C₆alkenyl, C₃-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₁₀ cycloalkylalkyl, eachoptionally substituted with 1 to 3 substituents independently selectedat each occurrence from C₁-C₆ alkyl, C₃-C₆ cycloalkyl, halo, C₁-C₄haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³,NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl,heteroaryl and heterocyclyl; R⁴ is independently selected at eachoccurrence from: C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₆cycloalkyl, C₄-C₁₂ cycloalkylalkyl, NO₂, halo, CN, C₁-C₄ haloalkyl,NR⁶R⁷, NR⁶COR⁷, NR⁶CO₂R⁷, COR⁷, OR⁷, CONR⁶R⁷, CO(NOR⁹)R⁷, CO₂R⁷, orS(O)_(n)R⁷, where each such C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀alkynyl, C₃-C₆ cycloalkyl and C₄-C₁₂ cycloalkylalkyl are optionallysubstituted with 1 to 3 substituents independently selected at eachoccurrence from C₁-C₄ alkyl, NO₂, halo, CN, NR⁶R⁷, NR⁶COR⁷, NR⁶CO₂R⁷,COR⁷ OR⁷, CONR⁶R⁷, CO₂R⁷, CO(NOR⁹)R⁷, or S(O)_(n)R⁷; R⁶ and R⁷ areindependently selected at each occurrence from: —H, —C₁-C₁₀ alkyl,C₃-C₁₀ alkenyl, C₃-C₁₀ alkynyl, C₁-C₁₀ haloalkyl with 1-10 halogens,C₂-C₈ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl, C₅-C₁₀cycloalkenyl, or C₆-C₁₄ cycloalkenylalkyl, each optionally substitutedwith 1 to 3 substituents independently selected at each occurrence fromC₁-C₆ alkyl, C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl, cyano, OR¹⁵, SH,S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵,NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroaryl or heterocyclyl, -aryl,aryl(C₁-C₄ alkyl), heteroaryl, heteroaryl(C₁-C₄ alkyl), heterocyclyl orheterocyclyl(C₁-C₄ alkyl); alternatively, NR⁶R⁷ is piperidine,pyrrolidine, piperazine, N-methylpiperazine, morpholine orthiomorpholine, each optionally substituted with 1-3 C₁-C₄ alkyl groups;R⁸ is independently selected at each occurrence from H or C₁-C₄ alkyloptionally substituted by halogen, C₁-C₄ alkoxy or C₁-C₄ halo-alkoxy (1to 4 halogens); R⁹ and R¹⁰ are independently selected at each occurrencefrom H, C₁-C₄ alkyl, or C₃-C₆ cycloalkyl; R¹¹ is selected from H, C₁-C₄alkyl, C₁-C₄ haloalkyl, or C₃-C₆ cycloalkyl; R¹² is C₁-C₄ alkyl or C₁-C₄haloalkyl; R¹³ is selected from C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₂-C₈alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₁₂ cycloalkylalkyl, aryl, aryl(C₁-C₄alkyl)-, heteroaryl or heteroaryl(C₁-C₄ alkyl)-; R¹⁵ and R¹⁶ areindependently selected at each occurrence from H, C₁-C₆ alkyl, C₃-C₁₀cycloalkyl, C₄-C₁₆ cycloalkylalkyl, except that for S(O)_(n)R¹⁵, R¹⁵cannot be H; aryl is phenyl or naphthyl, each optionally substitutedwith 1 to 5 substituents independently selected at each occurrence fromC₁-C₆ alkyl, C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl, cyano, OR¹⁵, SH,S(O)_(n)R¹⁵, COR¹⁵, CO₂R¹⁵, OC(O)R¹⁵, NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵,NR⁸CO₂R¹⁵, NR¹⁶R¹⁵, and CONR¹⁶R¹⁵; heteroaryl is pyridyl, pyrimidinyl,triazinyl, furanyl, pyranyl, quinolinyl, isoquinolinyl, thienyl,imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl,benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl,2,3-dihydrobenzothienyl or 2,3-dihydrobenzofuranyl, each beingoptionally substituted with 1 to 5 substituents independently selectedat each occurrence from C₁-C₆ alkyl, C₃-C₆ cycloalkyl, halo, C₁-C₄haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹⁵, —COR¹⁵, CO₂R¹⁵, OC(O)R¹⁵,NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹⁵, NR¹⁶R¹⁵, and CONR¹⁶R¹⁵;heterocyclyl is saturated or partially saturated heteroaryl, optionallysubstituted with 1 to 5 substituents independently selected at eachoccurrence from C₁-C₆ alkyl, C₃-C₆ cycloalkyl, halo, C₁-C₄ haloalkyl,cyano, OR¹⁵, SH, S(O)_(n)R¹⁵, COR¹⁵, CO₂R¹⁵, OC(O)R¹⁵, NR⁸COR¹⁵,N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹⁵, NR¹⁵R¹⁶, and CONR¹⁶R¹⁵; and n isindependently at each occurrence 0, 1 or
 2. 8. The method according toclaim 7 wherein Ar is phenyl or pyridyl, each optionally substitutedwith 1 to 4 R⁴ substituents.
 9. The method according to claim 7 whereinAr is phenyl wherein the phenyl is optionally substituted with 1 to 3 R⁴substituents.
 10. The method according to claim 7 wherein R² is: —C₁-C₁₀alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₈ cycloalkyl, C₅-C₈cycloalkenyl, C₄-C₁₂ cycloalkylalkyl or C₆-C₁₀ cycloalkenylalkyl, eachoptionally substituted with 1 to 3 substituents independently selectedat each occurrence from C₁-C₆ alkyl, C₃-C₆ cycloalkyl, halo, C₁-C₄haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³,NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl,heteroaryl and heterocyclyl.
 11. The method according to claim 7 whereinR¹, R² and R³ are independently selected from C₁₋₆ alkyl or C₁₋₆alkyloxy.
 12. The method of claim 7 for treating affective disorder,anxiety, depression, headache, irritable bowel syndrome, post-traumaticstress disorder, supranuclear palsy, immune suppression, Alzheimer'sdisease, gastrointestinal diseases, anorexia nervosa or other feedingdisorder, drug addiction, drug or alcohol withdrawal symptoms,inflammatory diseases, cardiovascular or heart-related diseases,fertility problems, human immunodeficiency virus infections, hemorrhagicstress, obesity, infertility, head and spinal cord traumas, epilepsy,stroke, ulcers, amyotrophic lateral sclerosis, hypoglycemia or adisorder the treatment of which can be effected or facilitated byantagonizing CRF.
 13. The method of claim 7 for treating affectivedisorder, anxiety, depression, anorexia nervosa, drug or alcoholwithdrawal symptoms, inflammatory diseases, stroke, or epilepsy.